Bifunctional degraders of interleukin-1 receptor-associated kinase and their therapeutic uses

Abstract

To provide a method for treating a disease.SOLUTION: The present disclosure provides bifunctional compounds as IRAK4 degraders via ubiquitin proteasome pathway, and methods for treating diseases modulated by IRAK4. As described in detail and specifically demonstrated herein, it has been surprisingly discovered that the present invention achieves remarkable effects, which could not have been readily anticipated by those skilled in the art based on the prior art.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 234,606, filed August 18, 2021, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention provides novel bifunctional compounds for proteolyzing interleukin-1 receptor-associated kinase 4 (IRAK4) and methods for treating diseases modulated by IRAK4. [Background technology]

[0003] 2. Description of Related Art Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine / threonine kinase that plays a key role in mediating Toll-like receptor (TLR) and interleukin-1 receptor (IL1R) signaling in immune cells, leading to the production of proinflammatory cytokines. IRAK4 functions as part of the mydosome, a large multiprotein complex that assembles at the plasma membrane upon ligand binding to TLR and IL1R receptors. The first step in mydosome assembly is the recruitment of the scaffolding protein MyD88, followed by IRAK4 binding to Myd88 via a homotypic death domain (DD) interaction. IRAK4 then undergoes autoactivation and subsequently phosphorylates the downstream kinases IRAK1 and IRAK2. As IRAK4 is the most upstream kinase in this complex, it is considered a "master regulator" of mydosome signaling. The importance of IRAK4 kinase function has been demonstrated in IRAK-4 kinase-dead mice, which are resistant to TLR-induced septic shock due to their inability to produce proinflammatory cytokines.

[0004] IRAK4 has also been reported to have kinase-independent scaffolding functions. For example, macrophages derived from IRAK4 kinase-dead mice can still activate NF-κB signaling via IL-1, TLR2, TLR4, and TLR7 stimulation. A similar scaffolding function has been demonstrated in human fibroblasts, where kinase-dead IRAK4 can restore IL-1-induced NF-κB signaling to levels comparable to those of wild-type IRAK4.

[0005] Therefore, IRAK4 can be targeted for degradation, thereby providing therapeutic opportunities for treating autoimmune, inflammatory, and neoplastic diseases. Specific degradation of IRAK4 can be achieved by using heterobifunctional small molecules to recruit IRAK4 to ubiquitin ligase, thereby promoting its ubiquitination and proteasomal degradation. For example, thalidomide derivatives such as lenalidomide or pomalidomide have been reported to recruit potential protein substrates to cereblon (CRBN), a component of the ubiquitin ligase complex. See, for example, International Publication No. WO 2019 / 099926, International Publication No. WO 2020 / 023851, International Application No. US 2021 / 018710, and U.S. Patent Application Publication No. 2019 / 0192668. There is a need to further develop therapeutic agents that target IRAK4. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] International Publication No. 2019 / 099926 [Non-patent document 2] International Publication No. 2020 / 023851 [Non-patent document 3] International Application No. US2021 / 018710 [Non-patent document 4] US Patent Application Publication No. 2019 / 0192668 Summary of the Invention

[0007] The present disclosure provides a bifunctional compound represented by formula (I):

[0008] [ka] or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 is 1 to 3 R a C optionally substituted with 1~10 Alkyl, 1 to 3 R a C optionally substituted with 3~10 Cycloalkyl or 1 to 3 R a 4-12 membered heterocyclyl optionally substituted with 1 to 3 R a is a 5-12 membered heteroaryl optionally substituted with L is -L1-L2-L3-L4-, and each L1, L2, L3 and L4 is independently a) 1 to 3 R b C optionally substituted with 3~12 cycloalkyl, b) 1 to 3 R b C optionally substituted with 6~12 aryl, c) 1 to 3 R b 4-12 membered heterocyclyl optionally substituted with d) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with e) direct binding; f) 1 to 3 R d C optionally substituted with 1~12 Alkylene chains, g) 1 to 3 R d C optionally substituted with 2~12 Alkenylene chains, h) 1 to 3 R d C optionally substituted with 2~12 Alkynylene chains, i) 1 to 6 ethylene glycol units; j) 1 to 6 propylene glycol units, or k) -C(O)-, -C(O)O-, -O- 、 -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )- or -OC(O)-O-, Each R a are independently halo, -CN, 1 to 3 R d C optionally substituted with 1~3 Alkyl, 1 to 3 R d C optionally substituted with 3~6 cycloalkyl, or -OR c and Each R b are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c , -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c, -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c , -S(O)R c , -S(O)(NH)R c , -S(O)2R c , or -S(O)N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R d and optionally substituted with Each R c are independently hydrogen or C 1~6 is alkyl, Each R d are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl or C 3~8 cycloalkyl or -OC optionally substituted with 1 to 3 fluoro 1~6 is alkyl, W is -C(R g )- or -N-, The B ring is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is selected from 1 to 3 R j optionally replaced by Each R j are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR g , -C(O)-R g, -C(O)OR g , -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g , -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g , -S(O)R g , -S(O)(NH)R g , -S(O)2R g , or -S(O)N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R k and optionally substituted with R g is hydrogen or C 1~6 is alkyl, Each R k are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl or C 3~8 cycloalkyl or -OC optionally substituted with 1 to 3 fluoro 1~6 It is alkyl.

[0009] As used herein, a bifunctional compound represented by formula (I)

[0010] [ka] or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 is 1 to 3 R a C optionally substituted with 1~10 Alkyl, 1 to 3 R a C optionally substituted with 3~10 Cycloalkyl or 1 to 3 R a 4-12 membered heterocyclyl optionally substituted with L is -L1-L2-L3-L4-, and each L1, L2, L3 and L4 is independently a) 1 to 3 R b C optionally substituted with 3~12 cycloalkyl, b) 1 to 3 R b C optionally substituted with 6~12 aryl, c) 1 to 3 R b 4-12 membered heterocyclyl optionally substituted with d) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with e) direct binding; f) 1 to 3 R d C optionally substituted with 1~12 Alkylene chains, g) 1 to 3 R d C optionally substituted with 2~12 Alkenylene chains, h) 1 to 3 R d C optionally substituted with 2~12 Alkynylene chains, i) 1 to 6 ethylene glycol units; j) 1 to 6 propylene glycol units, or k) -C(O)-, -C(O)O-, -O- 、 -N(Rc )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )- or -OC(O)-O-, Each R a are independently halo, -CN, 1 to 3 R d C optionally substituted with 1~3 Alkyl, 1 to 3 R d C optionally substituted with 3~6 cycloalkyl, or -OR c and Each R b are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c , -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c , -OC(O)-N(R c )(R c ), -Si(R c)3, -SR c , -S(O)R c , -S(O)(NH)R c , -S(O)2R c , or -S(O)N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R d and optionally substituted with Each R c are independently hydrogen or C 1~6 is alkyl, Each R d are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl or C 3~8 cycloalkyl or -OC optionally substituted with 1 to 3 fluoro 1~6 is alkyl, W is -C(R g )- or -N-, The B ring is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is selected from 1 to 3 R j optionally replaced by Each R j are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g , -C(O)-N(R g )(R g ), -N(Rg )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g , -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g , -S(O)R g , -S(O)(NH)R g , -S(O)2R g , or -S(O)N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R k and optionally substituted with R g is hydrogen or C 1~6 is alkyl, Each R k are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl or C 3~8 cycloalkyl or -OC optionally substituted with 1 to 3 fluoro 1~6 It is alkyl.

[0011] especially,

[0012] [ka] The moiety is a ligase harness moiety (LHM) that specifically targets CRBN ligase, which is utilized by the bifunctional compound to induce ubiquitination and subsequent proteasomal degradation of IRAK4.

[0013] In more specific embodiments, the B ring of the LHM has one of the following structures:

[0014] [ka] In more specific embodiments, the bifunctional compounds are Examples 1-147 described in the Examples.

[0015] A further embodiment provides a pharmaceutical composition comprising a compound of formula (I) or any one of its substructures and a pharmaceutically acceptable carrier.

[0016] In some embodiments, the compounds of formula (I) or pharmaceutical compositions thereof are useful as therapeutic agents for treating cancers such as lymphoma, leukemia, acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS).

[0017] In other embodiments, the compounds of formula (I) or pharmaceutical compositions thereof are useful as therapeutic agents for treating metabolic disorders such as diabetes (type I and type II diabetes), metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0018] In other embodiments, the compounds of formula (I) or pharmaceutical compositions thereof are useful as therapeutic agents for treating inflammatory disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, necrotizing enterocolitis, gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, inflammation associated with gastrointestinal infections including Clostridioides difficile (C. difficile), viral myocarditis, acute and chronic tissue injury, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, and kidney diseases including chronic kidney disease and diabetic kidney disease. DETAILED DESCRIPTION OF THE INVENTION

[0019] Disclosed are bifunctional compounds capable of recruiting IRAK4 to an E3 ubiquitin ligase for degradation, as well as methods for preparing and using the same. In particular, the bifunctional compounds typically comprise an IRAK4 binder covalently attached via a linker to a ligase harness moiety for targeting the ubiquitin ligase. Advantageously, targeted degradation of IRAK4 provides effective treatment or amelioration of disease states involving IRAK4 function.

[0020] Thus, as used herein, a bifunctional compound represented by formula (I)

[0021] [ka] or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 is 1 to 3 R a C optionally substituted with 1~10 Alkyl, 1 to 3 R a C optionally substituted with 3~10 Cycloalkyl or 1 to 3 R a 4-12 membered heterocyclyl optionally substituted with 1 to 3 R a is a 5-12 membered heteroaryl optionally substituted with L is -L1-L2-L3-L4-, and each L1, L2, L3 and L4 is independently a) 1 to 3 R b C optionally substituted with 3~12 cycloalkyl, b) 1 to 3 R b C optionally substituted with 6~12 aryl, c) 1 to 3 R b 4-12 membered heterocyclyl optionally substituted with d) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with e) direct binding; f) 1 to 3 R d C optionally substituted with 1~12 Alkylene chains, g) 1 to 3 R d C optionally substituted with 2~12 Alkenylene chains, h) 1 to 3 R d C optionally substituted with 2~12 Alkynylene chains, i) 1 to 6 ethylene glycol units; j) 1 to 6 propylene glycol units, or k) -C(O)-, -C(O)O-, -O- 、 -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )- or -OC(O)-O-, Each R a are independently halo, -CN, 1 to 3 R d C optionally substituted with 1~3 Alkyl, 1 to 3 R d C optionally substituted with 3~6 cycloalkyl, or -OR c and Each R b are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c , -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c , -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c , -S(O)R c , -S(O)(NH)R c , -S(O)2R c , or -S(O)N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R d and optionally substituted with Each R c are independently hydrogen or C 1~6 is alkyl, Each R d are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl or C 3~8 cycloalkyl or -OC optionally substituted with 1 to 3 fluoro 1~6 is alkyl, W is -C(R g )- or -N-, The B ring is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is selected from 1 to 3 R j optionally replaced by Each R j are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g , -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g , -OC(O)-N(R g )(R g ), -Si(R g )3, -SRg , -S(O)R g , -S(O)(NH)R g , -S(O)2R g , or -S(O)N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R k and optionally substituted with R g is hydrogen or C 1~6 is alkyl, Each R k are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl or C 3~8 cycloalkyl or -OC optionally substituted with 1 to 3 fluoro 1~6 It is alkyl.

[0022] One particular embodiment is a bifunctional compound of formula (I)

[0023] [ka] or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 is 1 to 3 R a C optionally substituted with 1~10 Alkyl, 1 to 3 R a C optionally substituted with 3~10 Cycloalkyl or 1 to 3 R a is a 4- to 12-membered heterocyclyl optionally substituted with L is -L1-L2-L3-L4-, and each L1, L2, L3 and L4 is independently a) 1 to 3 R b C optionally substituted with3~12 cycloalkyl, b) 1 to 3 R b C optionally substituted with 6~12 aryl, c) 1 to 3 R b 4-12 membered heterocyclyl optionally substituted with d) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with e) direct binding; f) 1 to 3 R d C optionally substituted with 1~12 Alkylene chains, g) 1 to 3 R d C optionally substituted with 2~12 Alkenylene chains, h) 1 to 3 R d C optionally substituted with 2~12 Alkynylene chains, i) 1 to 6 ethylene glycol units; j) 1 to 6 propylene glycol units, or k) -C(O)-, -C(O)O-, -O- 、 -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, - OC(O)-N(R c )- or -OC(O)-O-, Each R a are independently halo, -CN, 1 to 3 R d C optionally substituted with 1~3 Alkyl, 1 to 3 R d C optionally substituted with 3~6 cycloalkyl, or -OR c and Each R b are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c , -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c , -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c , -S(O)R c , -S(O)(NH)R c , -S(O)2R c , or -S(O)N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R d and optionally substituted with Each R c are independently hydrogen or C 1~6 is alkyl, Each R d are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro;1~6 Alkyl or C 3~8 cycloalkyl or OC optionally substituted with 1 to 3 fluoro 1~6 is alkyl, W is -C(R g )- or -N-, The B ring is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is selected from 1 to 3 R j optionally replaced by Each R j are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g , -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g , -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g , -S(O)R g , -S(O)(NH)R g , -S(O)2Rg , or -S(O)N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R k and optionally substituted with R g is hydrogen or C 1~6 is alkyl, Each R k are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl or C 3~8 cycloalkyl or -OC optionally substituted with 1 to 3 fluoro 1~6 It is alkyl.

[0024] IRAK4 binder The IRAK4 binder portion of the bifunctional compound of formula (I) has the following structure, where the wavy line indicates the bond attached to the remainder of the compound of formula (I):

[0025] [ka] In the formula, R 1 is 1 to 3 R a C optionally substituted with 1~10 Alkyl, 1 to 3 R a C optionally substituted with 3~10 Cycloalkyl, 1 to 3 R a 4-12 membered heterocyclyl optionally substituted with 1 to 3 R a is a 5-12 membered heteroaryl optionally substituted with

[0026] In more specific embodiments, R 1 teeth, a) Halo, -OH, -OC 1~4C optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and -CN 1~5 Alkyl, b) Halo, C 1~5 Alkyl, -OH, -OC 1~4 a 4- to 8-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and -CN; c) Halo, C 1~5 Alkyl, -OH, -OC 1~4 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and -CN 3~10 cycloalkyl, d) Halo, C 1~5 Alkyl, -OH, -OC 1~4 and 5-6 membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and -CN.

[0027] In still more specific embodiments, R 1 teeth, a) C optionally substituted with halo, -OH, or -CN 1~5 Alkyl, b) Halo, C 1~5 a 4-8 membered heterocyclyl optionally substituted with alkyl, -OH, or -CN; c) Halo, C 1~5 C optionally substituted with alkyl, -OH or -CN 3~10 It is cycloalkyl.

[0028] In more specific embodiments, R 1 is oxetane, tetrahydrofuran or tetrahydropyran, each of which is F, C 1~3 It may be optionally substituted with alkyl, -OH or -CN.

[0029] In some embodiments, R 1 is cyclobutyl, cyclohexyl, cyclopropyl, isoxazolyl or C 1~4 alkyl, each of which is F, C 1~3Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, -OH, -OCH3, or -CN.

[0030] In another more specific embodiment,

[0031] [ka] The moiety has one of the following structures (the wavy line indicates the bond attached to the thiadiazole moiety):

[0032] [ka]

[0033] In a further embodiment,

[0034] [ka] The moiety has one of the following structures (the wavy line indicates the bond attached to the thiadiazole moiety):

[0035] [ka]

[0036] Cereblon-targeting ligase harness moiety (LHM) The cereblon (CRBN) protein is a substrate-recognition subunit of two ubiquitously expressed and biologically important Cullin-RING E3 ubiquitin ligase complexes. The LHM of the compound of Formula (I) is utilized by bifunctional compounds to target CRBN, an E3 ligase, inducing ubiquitination and subsequent proteasomal degradation of IRAK4.

[0037] One embodiment provides a CRBN-targeting LHM having the following structure (the wavy line indicates the bond attached to the remainder of the compound of formula (I):

[0038] [ka] (In the formula, W is -C(R g )- or -N-, The B ring is C 6~12 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, each of which is selected from 1 to 3 R j optionally replaced by Each R j are independently hydrogen, oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloal Kill, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g , -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g , -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g , -S(O)R g , -S(O)(NH)R g , -S(O)2R g, or -S(O)N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R k and optionally substituted with R g is hydrogen or C 1~6 is alkyl, Each R k are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 Alkyl or C 3~8 cycloalkyl or -OC optionally substituted with 1 to 3 fluoro 1~6 It is alkyl.

[0039] In certain embodiments, the B ring has one of the following structures:

[0040] [ka]

[0041] In a preferred embodiment, W is -CH-.

[0042] In more specific embodiments, W is -CH- and the CRBN-targeting LHM has one of the following structures:

[0043] [ka]

[0044] In more specific embodiments, R j is hydrogen or halo (eg, fluoro).

[0045] In other embodiments, W is -N-.

[0046] In a more specific embodiment, W is -N- and the CRBN-targeting LHM has the structure:

[0047] [ka]

[0048] In a more specific embodiment, W is -N- and the CRBN-targeting LHM has the following structure:

[0049] [ka]

[0050] Linker The bifunctional compound of formula (I) comprises a linker moiety that couples the IRAK4 binder to the LHM. The structure (e.g., length or rigidity) of the linker moiety can affect the efficiency or selectivity of the degradation process. Typically, the linker moiety comprises multiple segments that contribute to the length and rigidity of the linker in addition to providing attachment points for the IRAK4 binder and the LHM, respectively.

[0051] In certain embodiments, the linker moiety (L) of formula (I) has up to four linker segments (L s , s is 1, 2, 3, or 4), each L1, L2, L3, and L4 independently represents: a) 1 to 3 R b C optionally substituted with 3~12 cycloalkyl, b) 1 to 3 R b aryl optionally substituted with c) 1 to 3 R b 4-12 membered heterocyclyl optionally substituted with d) 1 to 3 R b 5-12 membered heteroaryl optionally substituted with e) direct binding; f) 1 to 3 R d C optionally substituted with 1~12 Alkylene chains, g) 1 to 3 R d C optionally substituted with 2~12 Alkenylene chains, h) 1 to 3 R d C optionally substituted with 2~12 Alkynylene chains, i) 1 to 6 ethylene glycol units; j) 1 to 6 propylene glycol units, and k) -C(O)-, -C(O)O-, -O- 、 -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )- or -OC(O)-O- is a divalent moiety selected from In the formula, each R b are independently oxo, imino, sulfoximino, halo, nitro, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c , -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NRc S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c , -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c , -S(O)R c , -S(O)(NH)R c , -S(O)2R c , or -S(O) 2N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5- to 12-membered heteroaryl, and 4- to 12-membered heterocyclyl is selected from 1 to 3 R d and optionally substituted with Each R c are independently hydrogen or C 1~6 is alkyl, and Each R d are independently C optionally substituted with halo, oxo, —CN, —OH, or 1 to 3 fluoro; 1~6 C optionally substituted with alkyl or 1 to 3 fluoro 3~8 It is cycloalkyl.

[0052] In more specific embodiments, each L1, L2, L3, and L4 is independently a) 1 to 3 R b C optionally substituted with 4~12 cycloalkyl, b) 1 to 3 R b C optionally substituted with 6~12 aryl, c) 1 to 3 R b 4-12 membered heterocyclyl optionally substituted with d) 1 to 3 R b5-12 membered heteroaryl optionally substituted with e) direct binding; f) 1 to 3 R d C optionally substituted with 1~12 an alkylene chain, or g) C(O)-, -O-, -N(R c )- or -C(O)-N(R c )-.

[0053] Unless otherwise specified, divalent moieties described herein (e.g., L or L) are substituted or unsubstituted, provided that valences are satisfied. s ) are understood to be not limited to the orientation in which they are depicted. For example, for a given linker segment, e.g., -C(O)-NH-, the manner in which it is attached to the rest of the molecule can be in either orientation: i.e., -C(O)-NH- or -NH-C(O)-, provided that the attachment does not violate the rules of valence.

[0054] On the other hand, if L is a series of L s When represented by the formula (I), the directionality is such that a particular L s For example, linker segment L1 should be understood to couple directly to the IRAK4 binder moiety. Linker segment L4 should be understood to couple directly to the LHM.

[0055] One or more of the linker segments may be a direct bond, for example, in -L2-L3-L4-, when L3 is a direct bond, it effectively does not exist because L2 and L4 are directly bonded to each other.

[0056] In various specific embodiments, L is C 3~12 A ring selected from cycloalkyl, 6- to 15-membered aryl, 3- to 15-membered heterocyclyl, and 5- to 15-membered heteroaryl, each of which may be selected from up to three R d (as defined herein). In more specific embodiments, L is C 4~12A ring selected from cycloalkyl, 6- to 12-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl, each of which may be selected from up to three R d (as defined herein).

[0057] In various specific embodiments, L1 can be one of the following ring moieties:

[0058] [ka]

[0059] In other particular embodiments, L1 is

[0060] [ka] It could be.

[0061] In certain embodiments, -L2-L3-L4- is one of the following structures: -C(O)-, -(CH2) m -,

[0062] [ka] and In the formula, m is 1, 2, or 3; R c is H or C 1~3 It is alkyl.

[0063] In further specific embodiments, -L2-L3-L4- has one of the following structures:

[0064] [ka]

[0065] In more specific embodiments, L is one of the following structures:

[0066] [ka] and In the formula, R c is H or C 1~3 alkyl, and m is 1, 2, or 3.

[0067] In other more specific embodiments, L has one of the following structures:

[0068] [ka]

[0069] Construction of compounds of formula (I) The synthesis or construction of compounds of formula (I) can typically be carried out in multiple steps, including separate preparation of the IRAK4 binder and LHM moiety components, followed by linking the respective components via covalent bond formation. Generally speaking, either or both of the components may be linked to one or more linker precursors (L x The linker precursor can be prepared using one or more linker segments (L s ) and has a terminal reactive group for further coupling. The two components are finally coupled to form ( L segment), compounds of formula (I) can be obtained.

[0070] The following scheme illustrates the general approach to preparing the building blocks: Examples 1-147 are specific examples of formula (I) that have been synthesized and characterized by their respective physicochemical properties.

[0071] A. Preparation of IRAK4 binder constructs Several general schemes for preparing IRAK4 binder components are described herein.

[0072] [ka]

[0073] Compounds of formula 1.5 can be obtained according to the method shown in Scheme 1. Using a suitable catalyst (e.g., HCl) and a suitable solvent (e.g., EtOH), 1-aminopyrrole 1.1 can be condensed with a suitable coupling partner to produce substituted pyrrolo[1,2-b]pyridazine 1.2. Halogenation at the indicated position using a known halogenating reagent (e.g., NBS) can form intermediate 1.3, which can be further substituted with a suitable reagent (e.g., Selectfluor) via either CH activation or electrophilic aromatic substitution to produce intermediate 1.4. Halogen-metal exchange from -X to -M can be achieved using a suitable reagent (e.g., n-BuLi) or transition metal coupling using a palladium catalyst and metal source (e.g., B2Pin2, Me6Sn2, etc.) to give intermediate 1.5.

[0074] [ka]

[0075] Compounds of formula 2.3 can be obtained according to the method shown in Scheme 2. Acid 2.1 can be converted to the corresponding acylhydrazine using a coupling reagent (such as HATU) in the presence of a base (such as DIPEA). Cyclization of compound 2.2 can be achieved by heating in the presence of a thiolation reagent (such as Lawesson's reagent) to give compound 2.3.

[0076] [ka]

[0077] Compounds of formula 3.6 can be obtained according to the method shown in Scheme 3. Dihalopyridine 3.1 can be converted to compound 3.2 via substitution of one of the halogen groups (e.g., nucleophilic aromatic substitution). Further functionalization of compound 3.2 using a metal-containing heterocyclic species (e.g., compound 1.5) with an appropriate catalyst, such as a palladium catalyst, can provide compound 3.3. Halogenation at the indicated position using a known halogenating reagent (e.g., NBS) can form intermediate 3.4, which can be further substituted by a cross-coupling reaction using an appropriate catalyst, such as a palladium catalyst, to provide compound 3.5.

[0078] [ka]

[0079] Compounds of formula 4.2 can be made according to Scheme A4. Displacement of the halogen group of halothiadiazole 4.1 with a nucleophile (such as an amine) (e.g., nucleophilic aromatic substitution) can provide compound 2.3. Halogenation at the indicated position using known halogenating reagents (e.g., NBS) can form intermediate 4.2.

[0080] [ka]

[0081] Compounds of formula 3.5 can also be made according to Scheme A5. Halogen-metal exchange of -X to -M can be achieved using a suitable reagent (e.g., n-BuLi, etc.) or transition metal coupling using a palladium catalyst and a metal source (e.g., B2Pin2, Me6Sn2, etc.) to provide intermediate 5.1. Functionalization of compound 5.1 can be carried out using a cross-coupling reaction with compound 4.2 using an appropriate catalyst, such as a palladium catalyst, to provide compound 3.5.

[0082] Under scheme A5, Lx can be a ring bearing a reactive moiety, which can then be coupled to another linker segment. For example, a BOC-protected L x teeth,

[0083] [ka] Compound 4.2 may be

[0084] [ka] The resulting compound 3.5 is an L1 precursor, i.e., an IRAK4 binder component bearing a piperazine ring, which can be further coupled to another linker segment via the reactive secondary amine of the piperazine.

[0085] [ka]

[0086] Another method for accessing compound 3.5 is shown in Scheme A6. Starting from nicotinic acid 6.1, the corresponding acylhydrazine can be prepared using a coupling reagent (e.g., HATU) in the presence of a base (e.g., DIPEA). Cyclization of compound 6.3 can be achieved by heating in the presence of a thiolation reagent (e.g., Lawesson's reagent) to give compound 6.4. Compound 6.4 can be further functionalized using a metal-containing heterocyclic species (e.g., compound 1.5) with an appropriate catalyst, such as a palladium catalyst, to give compound 3.5.

[0087] In Scheme A6, L x may be a ring bearing a reactive moiety, which in turn may be coupled to another linker segment. For example, L x teeth,

[0088] [ka] (optionally in BOC-protected form during synthesis), and the resulting compound 3.5 is the L1 precursor, i.e., another IRAK4 binder building block bearing a bicyclo[2.2.2]octane ring, which can be further coupled to another linker segment via a reactive primary amine.

[0089] Specific examples of preparing intermediate IRAK4 binder components that are further coupled to LHMs are described in more detail below.

[0090] Intermediate A: 7-(5-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0091] [ka]

[0092] Step 1: To a solution of 2-bromo-4-fluoropyridine (30.0 g, 170 mmol, 1.00 equiv) in NMP (300 mL) was added DIEA (33.1 g, 255 mmol, 44.5 mL, 1.50 equiv) and tetrahydro-2H-pyran-4-amine (20.7 g, 204 mmol, 1.20 equiv), and the mixture was stirred at 110° C. for 1.5 h. The reaction mixture was poured into HO (500 mL) and extracted with methyl tert-butyl ether (500 mL). * 4). The combined organic layers were washed with saturated brine (500 mL * 6), and the organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 2-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-4-amine. The residue was used in the next step without further purification (46 g). LCMS: m / z=257.2 (M+H). +

[0093] Step 2: To the product from Step 1 (30.0 g, 101 mmol, 1.00 equiv.) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (35.5 g, 132 mmol, 1.30 equiv.) in DME (300 mL) was added KPO (2.00 M, 102 mL, 2.00 equiv.) and Pd(dppf)Cl·CHCl (8.29 g, 10.2 mmol, 0.100 equiv.) under N, and the mixture was stirred at 100 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by MPLC (SiO, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1, R f =0.10) to give 7-(4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (30.0 g, 93.5 mmol, 92.1% yield) as a yellow solid. LCMS: m / z=320.2 (M+H). +

[0094] Step 3: To a solution of 7-(4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (36.0 g, 106 mmol, 1.00 equiv.) in MeCN (758 mL) and DCM (758 mL) was added a solution of NBS (16.7 g, 93.6 mmol, 0.880 equiv.) in MeCN (127 mL) and DCM (127 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was filtered, the filter cake was collected, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by MPLC (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1, R f =0.60). The filter cake and the residue from MPLC were combined to give 7-(5-bromo-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (34.9 g, 85.8 mmol, 80.6% yield). LCMS: m / z=397.9 (M+H). +

[0095] Step 4: To a solution of 7-(5-bromo-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (34.9 g, 85.7 mmol, 1.00 equiv) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (43.5 g, 171 mmol, 2.00 equiv) in DMF (175 mL) and dioxane (350 mL) was added KOAc (25.2 g, 257 mmol, 3.00 equiv) and Pd(PPh)Cl (9.02 g, 12.9 mmol, 0.150 equiv) under N, and the mixture was stirred at 120 °C under N for 3 h. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (TFA conditions). The desired product (13.3 g, 25.5 mmol, 29.8% yield, TFA) was obtained as a yellow solid. LCMS: Product: m / z = 364.0 (M+H). +

[0096] Step 5: To a solution of 2,5-dibromo-1,3,4-thiadiazole (20.0 g, 82.0 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (18.3 g, 98.4 mmol, 1.20 equiv) in dioxane (200 mL), DIEA (21.2 g, 164 mmol, 28.5 mL, 2.00 equiv) was added, and the mixture was then stirred at 110° C. for 2 h. The mixture was cooled to 25° C., filtered, and the filter cake was dissolved in ethyl acetate (50.0 mL). * 2), and the filtrate was washed with brine (200 mL * 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue which was used in the next step without further purification. tert-Butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (31.8 g, crude) was obtained as a red solid. LCMS: m / z=294.8 (M+H). +

[0097] Step 6: To a solution of (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)boronic acid (6.00 g, 11.5 mmol, 1.00 equiv, TFA) and tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (4.23 g, 12.1 mmol, 1.05 equiv) in dioxane (315 mL) under N was added Pd(OAc) (518 mg, 2.3 mmol, 0.200 equiv), Xantphos (2.67 g, 4.6 mmol, 0.400 equiv) and CsCO (9.39 g, 28.8 mmol, 2.50 equiv). The mixture was stirred under N2 at 120 °C for 5 h. The reaction mixture was filtered and the filter cake was diluted with ethyl acetate (200 mL * The filtrate was filtered, the filter cake was collected, and the filtrate was added to water (500 mL) and collected. * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (6.00 g, 8.7 mmol, 75% yield) as a yellow solid, which was used in the next step without further purification.

[0098] Step 7: A mixture of tert-butyl 4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (6.00 g, 8.7 mmol, 1.00 equiv) in HCl / EtOAc (4.00 M, 52.4 mL, 24.2 equiv) and EtOAc (20.0 mL) was stirred at 25° C. for 2.5 hours. The reaction mixture was filtered, and the resulting filter cake was collected and concentrated under reduced pressure to afford the HCl salt of the title product (4.06 g, 7.2 mmol, 82.6% yield) as a yellow solid. LCMS: m / z=488.4 (M+H). + . 1H NMR:(400MHz,D2O)δ8.52(s,2H),8.19(s,1H),7.87(d,J=4.8Hz,1H),7.25(s,1H),7.14(d,J=5.2Hz,1H),3. 99-4.03(m,2H),3.91-3.95(m,4H),3.74(t,J=20.0Hz,2H),3.48-3.52(m,4H),2.12(d,J=11.2Hz,2H),1.66-1.78(m,2H).

[0099] Intermediate B: 7-(4-(isopropylamino-5-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0100] [ka]

[0101] Intermediate B was prepared in a similar manner to Intermediate A, using tetrahydro-2H-pyran-4-amine instead of isopropyl-amine in step 1 to afford the HCl salt of the title product as a yellow solid. LCMS: m / z=446.2 (M+H). + . 1 H NMR:(400MHz,MeOD)δ8.77(d,J=2.0Hz,1H),8.69(d,J=2.4Hz,1H),8.56(s,1H),8.10(d,J=5.2Hz,1H),7.90(s,1H),7.2 4(d,J=4.8Hz,1H),4.32-4.29(m,1H),3.97-3.94(d,J=10.4Hz,4H),3.48-3.44(d,J=14.4Hz,4H),1.48(d,J=6.4Hz,6H).

[0102] Intermediate B: Alternate Route:

[0103] [ka]

[0104] Step 1: To a solution of 2-bromo-1,3,4-thiadiazole (7.29 g, 42.4 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (19.75 g, 106 mmol, 2.5 equiv) in n-butanol (83 mL, 0.51 M) was added N,N-diisopropylethylamine (29.56 mL, 16968 mmol, 4.0 equiv). The reaction mixture was stirred at 120 °C for 1 h. The reaction mixture was cooled and concentrated in vacuo. The resulting crude material was purified by chromatography eluting with EtOAc in hexanes (0-70% gradient) to give tert-butyl 4-(1,3,4-thiadiazole- 2-yl)piperazine-1-carboxylate was obtained as a pale red solid (9.93 g, 86% yield). LCMS: ESI(+)[M-tBu] + =215.26. 1 H NMR (300MHz, DMSO-d6) δ8.84 (s, 1H), 3.46 (m, 8H), 1.42 (s, 9H).

[0105] Step 2: 7-{5-bromo-4-[(propan-2-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.50 g, 15.4 mmol, 1.0 equiv.), tert-butyl 4-(1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (3.95 g, 13.9 mmol, 0.9 equiv.), palladium(II) acetate (0.173 g, 0 A mixture of CsCO (10.06 g, 30.88 mmol, 2.0 equiv.), CuI (0.294 g, 1.5 mmol, 0.10 equiv.), Xantphos (0.893 g, 1.54 mmol, 0.1 equiv.), and CsCO (10.06 g, 30.88 mmol, 2.0 equiv.) was placed in a pressure vessel equipped with a magnetic stirrer, followed by dimethoxyethane (250 mL, 0.061 M), degassed in vacuo, and backfilled with argon (5 times). The reaction mixture was stirred at 105 °C for 24 h. After cooling, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude material was purified by FC eluting with DCM / EtOAc (gradient 0-30%) followed by recrystallization from 96% EtOH to give tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(propan-2-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow solid (2.271 g, 27% yield). LCMS: ESI(+) [M+H] + =546.70. 1 H NMR(300MHz,CDCl3)δ8.76(s,1H),8.51(s,1H),8.36(s,1H),8.21(d,J=2.1Hz,1H),8.18(s,1H),8.02 (s,1H),7.02(d,J=4.8Hz,1H),3.99(h,J=6.4Hz,1H),3.63(s,8H),1.51(s,9H),1.43(d,J=6.4Hz,6H).

[0106] Step 3: tert-Butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(propan-2-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (2.27 g, 4.2 mmol, 1.0 equiv.) and 1,1,1,3,3,3-hexafluoro-2-propanol (6.57 mL, 62.4 mmol, 15 equiv.) were placed in a microwave reactor and stirred at 140° C. for 3 hours. The solvent was then evaporated in vacuo. The resulting residue was purified by chromatography eluting with MeOH / DCM to give the title compound as a yellow solid (1.615 g, 87% yield). LCMS: ESI(+) [M+H] + =446.03. 1 H NMR(300MHz,DMSO-d6)δ8.83(d,J=2.3Hz,1H),8.72(d,J=2.2Hz,1H),8.55(d,J=7.1Hz,1H),8.47(s,1H),8.19(s,1H),7.83 (d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),3.92(h,J=6.4Hz,1H),3.51-3.41(m,4H),2.88-2.79(m,4H),1.35(d,J=6.3Hz,6H).

[0107] Intermediate C: 7-(4-(methylamino)-5-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0108] [ka]

[0109] Step 1: To a solution of 2-bromo-4-fluoropyridine (30.0 g, 170 mmol, 1.00 equiv.) in NMP (300 mL) was added methanamine hydrochloride (13.8 g, 204 mmol, 1.20 equiv.) and DIEA (66.1 g, 511 mmol, 89.1 mL, 3.00 equiv.). The reaction mixture was then stirred at 110° C. for 2 h. The reaction mixture was poured into HO (600 mL) and diluted with DCM (200 mL). * The organic layer was extracted with saturated NaCl solution (200 mL * 6). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-bromo-N-methylpyridin-4-amine (29.2 g, crude) as a yellow liquid, which was used in the next step without purification. LCMS: m / z=188.9 (M+H). +

[0110] Step 2: To a solution of 2-bromo-N-methylpyridin-4-amine (19.2 g, 102 mmol, 1.00 equiv.) in DME (250 mL) was added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (31.7 g, 118 mmol, 1.15 equiv.), XPhos Pd G3 (9.60 g, 11.3 mmol, 0.110 equiv.), and K3PO4 (2.00 M, 102 mL, 2.00 equiv.). The reaction mixture was stirred under N2 at 100 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to give 7-(4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (16.9 g, 67.5 mmol, 65.7% yield) as a yellow solid. LCMS: m / z = 250.0 (M+H). +

[0111] Step 3: To a solution of 7-(4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (16.9 g, 67.5 mmol, 1.00 equiv) in DCM (355 mL) and ACN (355 mL) was added a solution of NBS (10.6 g, 59.4 mmol, 0.88 equiv) in DCM (177 mL) and ACN (177 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with petroleum ether (30.0 mL) at 25° C. for 30 min to give 7-(5-Bromo-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (28.4 g, 75.0 mmol) was obtained as a yellow solid. LCMS: m / z=329.9 (M+H) +

[0112] Step 4: To a solution of 7-(5-bromo-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (24.2 g, 63.9 mmol, 1.00 equiv.) in dioxane (242 mL) and DMF (121 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (32.5 g, 127 mmol, 2.00 equiv.), KOAc (18.8 g, 191 mmol, 3.00 equiv.), and Pd(PPh)Cl (6.71 g, 9.6 mmol, 0.150 equiv.) under N. The reaction mixture was stirred at 120 °C for 1 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC (0.1% TFA) to give (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridin-3-yl)boronic acid (12.93 g, 29.7 mmol, 46.4% yield, TFA) as a yellow solid. LCMS: m / z = 293.9 (M+H). +

[0113] Step 5: To a solution of (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridin-3-yl)boronic acid (4.00 g, 9.2 mmol, 1.00 equiv., TFA) in dioxane (210 mL) was added tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (3.39 g, 9.6 mmol, 1.05 equiv.), CsCO (7.47 g, 22.9 mmol, 2.50 equiv.), Xantphos (2.12 g, 3.67 mmol, 0.40 equiv.), and Pd(OAc) (412 mg, 1.8 mmol, 0.20 equiv.) under N. The reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was directly filtered at 120° C., the filter cake was washed with DCM (30.0 mL), and the filtrate was concentrated in vacuo to give a residue. The residue was triturated with EtOAc (30.0 mL) at 25° C. for 30 minutes to give tert-butyl 4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (5.60 g, crude) as a yellow solid. LCMS: m / z=518.1 (M+H). + . 1 H NMR:(400MHz,CDCl3)δ8.53(s,1H),8.35(d,J=2.4Hz,1H),8.19(d,J=2.0Hz,1H),8.10(s,1H), 7.92(d,J=4.8Hz,1H),6.99(s,1H),3.62(d,J=1.6Hz,8H),3.12(d,J=4.8Hz,3H),1.49(s,9H).

[0114] Step 6: To a solution of tert-butyl 4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (5.60 g, 10.8 mmol, 1.00 equiv) in EtOAc (28.0 mL) was added HCl / EtOAc (4.00 M, 28.0 mL, 10.3 equiv). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered, and the filter cake was washed with DCM (50.0 mL) and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (basic conditions) to give 7-(4-(methylamino)-5-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.13 g, 2.6 mmol, 24.2% yield) as a yellow solid. LCMS: m / z=418.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.0Hz,1H),8.72(d,J=2.0Hz,1H),8.51-8.47(m,2H ),8.14(s,1H),7.85(d,J=5.2Hz,1H),7.12(d,J=4.4Hz,1H),3.45(t,J=4.8Hz,4H),3. 06(d,J=4.8Hz,3H),2.83(t,J=5.2Hz,4H).

[0115] Intermediate C: Alternate Route

[0116] [ka]

[0117] Step 1: To a mixture of 2-bromo-4-fluoro-pyridine (25.0 g, 0.142 mol, 1.0 eq) was added methylamine (9.8 M) in methanol (142 mL, 1.42 mol, 10 eq) and the resulting mixture was heated at 80 °C overnight. Upon completion, the reaction mixture was cooled and all volatiles were evaporated in vacuo, dissolved in EtOAc, and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 2-bromo-N-methylpyridin-4-amine (25 g, 89% yield). 1 H NMR (300MHz, DMSO-d6), δ:7.77(d,J=5.8Hz,1H),6.98-6.78(m,1H),6.59(m,1H),6.48(m,1H),2.69(d,J=4.9Hz,3H). LCMS:ESI(+)[M+H] + =188.94.

[0118] Step 2: To a solution of 2-bromo-N-methylpyridin-4-amine (6.0 g, 32.1 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (12.09 g, 44.9 mmol, 1.4 equiv.), and Xphos G3 (2.17 g, 2.6 mmol, 0.08 equiv.) in anhydrous dimethoxyethane (80 mL, 0.4 M) was added 2 M aqueous KPO (32.1 mL, 64.2 mmol, 2.0 equiv.). The solution was degassed with argon for 15 minutes and then heated at 120 °C overnight with vigorous stirring. The reaction mixture was filtered through a pad of Celite and evaporated to dryness under reduced pressure. The crude residue obtained was purified by chromatography using methanol (0-10%) in dichloromethane to give 7-[4-(methylamino)-2-pyridyl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid (6.1 g, 76% yield). 1H NMR(300MHz,DMSO-d6),δ:8.79(d,J=2.2Hz,1H,),8.64(d,J=2.2Hz,1H,),8.19(d,J=5.6,1H,),7.87 (d,J=2.3,1H,),7.76(d,J=4.7Hz,1H,),7.08(d,J=4.7,1H,),6.80(d,J=5.0,1H,),6.45(m,1H,),2.7 7(d,J=4.8Hz,3H). LCMS:ESI(+)[M+H] + =250.36.

[0119] Step 3: 7-[4-(methylamino)-2-pyridyl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.3 g, 20.1 mmol, 1.0 equiv.) was dissolved in acetonitrile (65 mL, 0.3 M) and dichloromethane (20 mL, 0.7 M), and N-bromosuccinimide (3.57 g, 20.1 mmol, 1.0 equiv.) was added in one portion at room temperature. The reaction was stirred at ambient conditions for 30 minutes. The reaction progress was monitored by LCMS. Upon completion, the mixture was evaporated under reduced pressure, and the resulting residue was purified by chromatography using 0-5% ethyl acetate in dichloromethane to afford 7-(5-bromo-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid (5.95 g, 88% yield). 1 H NMR(300MHz,DMSO-d6),δ:8.80(d,J=2.2Hz,1H),8.67(d,J=2.2Hz,1H),8.36(s,1H),7.94(s,1 H),7.76(d,J=4.8Hz,1H),7.08(d,J=4.8Hz,1H),6.45(q,J=4.3Hz,1H),2.90(d,J=4.7Hz,3H). LCMS:ESI(+)[M+H] + =330.16.

[0120] Step 4: tert-Butyl 4-(1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate was prepared in a similar manner as in Step 1 of Intermediate B (alternative route). 1H NMR (300MHz, DMSO-d6), δ: 8.84 (s, 1H), 3.46 (s, 8H), 1.42 (s, 9H). LCMS:ESI(+)[M+2H] + =272.16.

[0121] Step 5: 7-[5-bromo-4-(methylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.5 g, 1.52 mmol, 1.0 equiv.), palladium(II) acetate (0.051 g, 0.23 mmol, 0.15 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.26 g, 0.5 mmol, 0.3 equiv.), cesium carbonate A mixture of 1,3,4-thiadiazol-2-ylpiperazine-1-carboxylate (0.434 g, 1.5 mmol, 1 equiv.) and copper(I) iodide (0.087 g, 0.5 mmol, 0.3 equiv.) was placed in an oven-dried screw-cap vial, and tert-butyl-4-(1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (0.434 g, 1.5 mmol, 1 equiv.) and anhydrous dioxane (25.39 mL, 0.06 M) was added. The reaction tube was evacuated and backfilled with argon for 20 min, sealed, and stirred at 105 °C overnight. After completion of the reaction (confirmed by UPLC), all volatiles were evaporated in vacuo and the resulting residue was purified by chromatography (0–31% ethyl acetate in dichloromethane) to afford tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)-pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow crystalline solid (0.57 g, 61% yield). 1 H NMR(300MHz,DMSO-d6),δ:8.83(s,1H),8.73(s,1H),8.48(m,2H),8.14(s,1H),7. 86(s,1H),7.12(d,J=4.8Hz,1H),3.54(s,8H),3.06(d,J=4.9Hz,3H),1.44(s,9H). LCMS:ESI(+)[M+H] + =518.64.

[0122] Step 6: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)-pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (0.25 g, 0.5 mmol, 1 equiv) in 1,1,1,3,3,3-hexafluoro-2-propanol (0.769 mL, 7.3 mmol, 15 equiv) was heated at 140° C. for 3 h using MW. All volatiles were then evaporated under reduced pressure and the remaining residue was purified by chromatography (0-7% methanol in dichloromethane) to give the title product as a yellow solid (0.15 g, 73% yield). LCMS: ESI(+) [M+H] + =418.06. 1 H NMR(300MHz,DMSO-d6),δ:8.83(d,J=2.2Hz,1H),8.72(s,1H),8.54-8.42(m,2H),8.13(s,1H),7.85( d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),3.46(s,4H),3.06(d,J=4.9Hz,3H),2.84(s,4H),2.61(m,1H).

[0123] Intermediate D: 7-[5-(5-{4-formylbicyclo[2.2.2]octan-1-yl}-1,3,4-thiadiazol-2-yl)-4-[(oxan-4-yl)amino]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0124] [ka]

[0125] Step 1: A solution of methyl 4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (6 g, 13 mmol, 1 equiv.) in anhydrous THF (324.5 mL, 0.04 M) was cooled to −15° C. under an argon atmosphere and treated with DIBAL-H (38.96 mL of a 1.0 M solution in THF, 39 mmol, 3 equiv.). After 30 min, the cooling bath was removed, and the mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched by the addition of MeOH (40 mL) and stirred vigorously for 20 min, followed by the addition of a saturated aqueous solution of Rochelle's salt. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-10%, acetone / DCM) to give [4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]-octan-1-yl]methanol as an off-white solid (3.65 g, 65% yield). LCMS: ESI(+) [M+H] + =435.54. 1 H NMR(300MHz,DMSO-d6),δ:8.91(d,J=7.7Hz,1H),8.42(s,1H),7.05(s,1H),4.46(t,J=5.4Hz,1H),3.8 6(m,3H),3.52(t,J=11.0Hz,2H),3.14(dd,J=20.1,5.3Hz,2H),2.00-1.87(m,8H),1.55-1.39(m,8H).

[0126] Step 2: To a solution of [4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]-octan-1-yl]methanol (3.78 g, 8.3 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.70 g, 9.9 mmol, 1.2 equiv) and Pd(dppf)Cl.CHCl (1.69 g, 2.1 mmol, 0.25 equiv) in anhydrous dioxane (212 mL, 0.04 M) was added 2 M aqueous KCO (8.5 mL, 16.6 mmol, 2.0 equiv). The mixture was degassed with argon for 30 min. The mixture was evaporated and then stirred at 120°C overnight. The reaction mixture was diluted with DCM, filtered through a pad of Celite, washed with DCM / MeOH (1:1), and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (DCM / acetone) to give [4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl]methanol (3.3 g, 73% yield). LCMS: ESI(+) [M+H] + =542.67. 1 H NMR(300MHz,DMSO-d6),δ:8.84(m,3H),8.69(s,1H),8.32(s,1H),7.86(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),4.46(t ,J=5.4Hz,1H),3.94(d,J=15.3Hz,3H),3.60(t,J=10.2Hz,2H),3.11(d,J=5.4Hz,2H),2.11-1.88(m,9H),1.49(s,8H).

[0127] Step 3: To a solution of [4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl]methanol (3.3 g, 6.1 mmol, 1 equiv.) in DCM (609 mL, 0.01 M) was added Dess-Martin periodinane (3.36 g, 8.0 mmol, 1.3 equiv.). The reaction mixture was stirred at room temperature for 2 h, after which it was quenched with 20% aqueous NaSO and saturated aqueous NaHCO. The resulting mixture was stirred until the aqueous layer became clear. The latter was then extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO, water, and brine, dried over NaSO, and concentrated under reduced pressure. The crude product was triturated with Et2O, filtered off, and washed on the filter with a mixture of DCM / Et2O (1:1), Et2O and pentane to give the title compound (2.8 g, 84% yield). LCMS: ESI(+) [M+H] + =540.20. 1 H NMR(300MHz,DMSO-d6),δ:9.49(s,1H),8.90-8.73(m,3H),8.70(s,1H),8.32(s,1H),7.86(d,J=4.8Hz,1H),7.12(d,J=4.8Hz) ,1H),3.95(d,J=11.7Hz,3H),3.60(t,J=10.3Hz,2H),2.18-1.96(m,8H),1.78(d,J=8.1Hz,6H),1.60(q,J=11.9,9.9Hz,2H).

[0128] Intermediate E: 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]bicyclo[2.2.2]octane-1-carboxylic acid.

[0129] [ka]

[0130] Step 1: DIPEA (220 mL, 1.26 mol, 2.6 equiv.) was dissolved in ACN (486 To a cooled, stirred solution of methyl 4,6-dichloronicotinate (100 g, 485 mmol, 1.0 equiv.) in 1 mL (1M). Tetrahydro-2H-pyran-4-amine (65 mL, 631 mmol, 1.3 equiv.) was added dropwise, and the mixture was stirred at 70° C. for 36 h. The mixture was cooled, the solids were filtered off, and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was recrystallized from hexane to give methyl 6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carboxylate (124.8 g, 92% yield). LCMS: ESI(+) [M+H] + =272.25. 1 H NMR(300MHz,DMSO-d6)δ:8.54(s,1H),8.06(d,J=7.9Hz,1H),7.00(s,1H),3.84(s,6H) ),3.48(td,J=11.4,2.0Hz,2H),1.90(d,J=10.7Hz,2H),1.46(qd,J=11.1,4.5Hz,2H).

[0131] Step 2: To a solution of methyl 6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carboxylate (40 g, 147.7 mmol, 1.0 equiv.) in EtOH (246 mL), hydrazine monohydrate 65% by weight (88 mL, 1.18 mol, 8.0 equiv.) was added and the mixture was stirred at 80° C. for 2 h. The volatiles were evaporated and then coevaporated with toluene several times. The residue was dried overnight at 50° C. and 5 mBar to give 6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carbohydrazide (37.6 g, 89% yield). LCMS: ESI(+) [M+H] + =272.05. 1 H NMR(300MHz,DMSO-d6)δ:9.87(s,1H),8.40(d,J=7.8Hz,1H),8.27(s,1H),6.84(s,1H),4.49(s,2H),3.91 -3.78(m,2H),3.77-3.64(m,1H),3.58-3.39(m,2H),1.89(d,J=12.1Hz,2H),1.39(qd,J=10.7,4.2Hz,2H).

[0132] Step 3: To a solution of monomethyl-1,4-cyclohexanedicarboxylate (31 g, 146 mmol, 1.1 equiv.) in DMF (460 mL) was added DIPEA (70 mL, 399 mmol, 3.0 equiv.) and HATU (60.7 g, 159.6 mmol, 1.2 equiv.), followed by portionwise addition of 6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carbohydrazide (37.6 g, 133 mmol, 1.00 equiv.). The mixture was stirred at 25 °C for 1.5 h. The reaction was quenched with water and ice (600 mL) and extracted with EtOAc. The organic layer was washed with aqueous NaHCO3, aqueous KHSO4, water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with DCM / MeOH (0-10%) to give methyl 4-(N'-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carbonyl}hydrazinecarbonyl)bicyclo[2.2.2]octane-1-carboxylate (45 g, 72% yield). LCMS: ESI(+) [M+H] + =465.5. 1 H NMR(300MHz,DMSO-d6)δ:10.30(s,1H),9.51(s,1H),8.39(s,1H),8.29(d,J=7.9Hz,1H),6.90(s,1H),4.10(d,J=4.8Hz,1H),3.90-3.78(m ,2H),3.78-3.66(m,1H),3.59(s,3H),3.55-3.38(m,2H),3.17(d,J=4.0Hz,2H),1.88(d,J=10.8Hz,2H),1.76(s,12H),1.49-1.30(m,2H).

[0133] Step 4: To a solution of methyl 4-(N'-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carbonyl}hydrazinecarbonyl)bicyclo[2.2.2]octane-1-carboxylate (45 g, 1 equiv.) in anhydrous THF (0.06 M) was added Lawesson's reagent (1.5 equiv.) portionwise with vigorous stirring at 40 °C. The resulting suspension was stirred at 75 °C for 2 h. Upon completion, the volatiles were evaporated and the residue was dissolved in DCM. The resulting solution was washed with aqueous KCO and concentrated under reduced pressure. The crude material was purified by chromatography (EtOAc in DCM, 0-10%) to give methyl 4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (15.6 g, 35% yield). LCMS: ESI(+) [M+H] + =463.6. 1 H NMR(300MHz,DMSO-d6)δ:8.89(d,J=7.8Hz,1H),8.44(s,1H),7.06(s,1H),3.98-3.71 (m,3H),3.62(s,3H),3.52(t,J=10.1Hz,2H),2.09-1.77(m,14H),1.58-1.38(m,2H).

[0134] Step 5: Methyl 4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (5 g, 10.8 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.78 g, 14 mmol, 1.3 equiv) and CsOAc (6.4 g, 32.4 mmol, 3 equiv) were dissolved in anhydrous THF (216 mL, 0.05 M). The solution was degassed with argon for 15 minutes, and then [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.22 g, 2.7 mmol, 0.25 equiv.) was added. The pressure vessel was sealed and stirred at 90 °C overnight. The reaction was filtered through a pad of Celite and washed with DCM and MeOH. The solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (5–50%, DCM in ACN) to give methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (5.1 g, 80% yield). LCMS: ESI (+) [M+H] + =570.69. 1 H NMR(300MHz,DMSO-d6)δ:8.86(d,J=2.2Hz,1H),8.81(d,J=7.1Hz,1H),8.79(d,J=2.2Hz,1H),8.71(s,1H),8.34(s,1H),7.86(d,J=4. 9Hz,1H),7.13(d,J=4.8Hz,1H),4.04-3.81(m,3H),3.67-3.45(m,5H),2.21-2.08(m,2H),2.07-1.80(m,12H),1.60(q,J=10.1Hz,2H).

[0135] Step 6: To a solution of methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (4.1 g, 7.2 mmol, 1 equiv.) in pyridine (72 mL, 0.1 M), lithium iodide (9.73 g, 72 mmol, 10 equiv.) was added, and the resulting mixture was stirred at 150 °C for 20 h. The reaction mixture was concentrated in vacuo and acidified with an equimolar amount of dilute HCl. The resulting residue was purified by column chromatography (0-15%, IPA / DCM) to afford the title compound (1.25 g, 30% yield). LCMS: ESI(+) [M+H] + =556.20. 1 H NMR(300MHz,DMSO-d6)δ:12.22(s,1H),9.51(s,1H),8.96(d,J=2.1Hz,1H),8.86(d,J=2.2Hz,1H),8.77(s,1H),8.16(s,1H),8.03(d, J=5.0Hz,1H),7.22(d,J=4.9Hz,1H),4.08(s,1H),4.01-3.89(m,2H),3.60(t,J=10.2Hz,2H),2.16-1.78(m,14H),1.75-1.56(m,2H).

[0136] Intermediate F: 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)-4-(oxan-4-ylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0137] [ka]

[0138] The title compound was synthesized according to the same procedure as described for Intermediate T, except that tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. LCMS C 26 H 27 N9OS theoretical value: 513.2, measured value: m / z = 514.3 [M+H] + .

[0139] Intermediate G: 7-[5-(5-{2,7-diazaspiro[3.5]nonan-2-yl}-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0140] [ka]

[0141] Step 1: A suspension of 2,5-dibromo-1,3,4-thiadiazole (970 mg, 4.0 mmol, 1.0 equiv), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (990 mg, 4.4 mmol, 1.1 equiv), and DIPEA (1.038 mL, 4.6 mmol, 1.5 equiv) in dioxane (15 mL, 0.21 M) was stirred at 120 °C for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The crude material was purified by flash chromatography eluting with hexane / EtOAc to give the desired compound as a yellow oil (1.54 g, 96% yield). LCMS: ESI(+) [M+H] + =391.3 1 H NMR (300 MHz, DMS O-d6)δ3.83(s,4H),3.31-3.21(m,4H),1.75-1.62(m,4H),1.39(s,9H).

[0142] Step 2: 7-[5-Bromo-4-(methylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carboxylic acid nitrile (1.5 g, 4.6 mmol, 1.0 equiv.) was dissolved in dioxane (25 mL) in a pressure vessel, followed by the addition of bis(pinacolato)diboron (1.39 g, 5.49 mmol, 1.2 equiv.) and KOAc (0.89 g, 9.14 mmol, 2.0 equiv.). The solution was sparged with argon for 7 minutes, and Pd(dppf)Cl·DCM (0.375 g, 0.46 mmol, 0.1 equiv.) was added, followed by further sparging. The reaction mixture was then transferred to a preheated oil bath and stirred at 90 °C overnight. UPLC indicated product formation. The reaction mixture was filtered through a Celite cake and evaporated to dryness. The crude material was used in the next step without further purification. LCMS: ESI(+)[M+H] + =294.2.

[0143] Step 3: To a solution of tert-butyl 2-(5-bromo-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.377 g, 2.57 mmol, 1.0 equiv) and 7-[4-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.0 g, 2. mmol, 1.0 equiv) in dioxane (13 mL, 0.2 M) in a pressure vessel was added cesium carbonate (2.09 g, 6.42 mmol, 2.5 equiv) and palladium(II) acetate (0.115 g, 0.51 mmol, 0.2 equiv). The reaction was sparged with argon for 7 minutes, followed by the addition of Xantphos (0.59 g, 1.03 mmol, 0.4 equiv). The solution was degassed with argon for an additional 3 minutes and then stirred at 120 °C overnight. LCMS showed the formation of the product. The reaction mixture was filtered through a celite cake and evaporated to dryness. The crude was purified by column chromatography eluting with DCM / MeOH (0-10%) to give 0.415 g (29% yield) of the desired product. LCMS: ESI (+) [M+H] + =558.8. 1H NMR(300MHz,DMSO-d6)δ8.83(d,J=2.2Hz,1H),8.73(d,J=2.2Hz,1H),8.48(s,2H),8.14(s,1H),7.85(d,J= 4.8Hz,1H), 7.12(d,J=4.8Hz,1H),3.91(s,4H),3.06(d,J=4.8Hz,3H),1.75(t,J=5.6Hz,4H),1.40(s,9H).

[0144] Step 4: Tert-butyl 2-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.2 g, 0.36 mmol, 1.0 equiv.) was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (1.13 mL, 30 equiv.) in a sealed reactor and placed in a microwave at 150 °C for 2 h. UPLC indicated complete deprotection of the starting material. The solvent was evaporated to dryness, and the solid was triturated with EtO to give 146 mg (87% yield) of the desired product as a yellow solid. LCMS: ESI(+) [M+H] + =458.08. 1 H NMR(300MHz,DMSO-d6)δ8.83(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.47(s,2H),8.13(s,1H),7.85(d,J=4. 8Hz,1H), 7.12(d,J=4.8Hz,1H),3.86(s,4H),3.06(d,J=4.8Hz,3H),2.63(t,J=5.4Hz,4H),1.87-1.60(m,4H).

[0145] Intermediate H: 7-(5-(5-([4,4'-bipiperidin]-1-yl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0146] [ka]

[0147] The title compound was synthesized according to the same procedure as described for Intermediate T, except that tert-butyl [4,4'-bipiperidine]-1-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. LCMS C 26 H 29 N9S theoretical value: 499.2, actual value: m / z = 500.4 [M+H] + .

[0148] Intermediate I: 7-[4-(methylamino)-5-{5-[(1r,4r)-4-(methylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0149] [ka]

[0150] Step 1: Methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (3.0 g, 11.66 mmol, 1.0 equiv) was dissolved in DMF (20 mL, 0.6 M) and cooled to 0 °C. NaH (0.536 g, 13.99 mmol, 1.2 equiv) was then added, and the reaction mixture was stirred at 0 °C for 30 min. Methyl iodide (1.09 mL, 17.49 mmol, 1.5 equiv) was then added, and the cooling bath was then removed, and the reaction mixture was stirred at room temperature overnight. TLC showed the formation of a new spot, so the mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The crude material was purified with hexane:EtOAc to give 1.4 g (44% yield) of the desired product. 1 H NMR(300MHz,DMSO-d6)δ3.58(s,3H),2.64(s,3H),2.25(tt,J=11.7,3.6Hz,1 H),1.94(dt,J=12.3,2.6Hz,2H),1.60-1.41(m,4H),1.38(d,J=1.6Hz,12H).

[0151] Step 2: Methyl (1r,4r)-4-{[(tert-butoxy)carbonyl](methyl)amino}cyclohexane-1-carboxylate (1.3 g, 4.79 mmol, 1 The resulting mixture (0.0 equiv.) was dissolved in THF (18 mL, 0.27 M), followed by the addition of a solution of LiOH (4.8 mL, 4.79 mmol, 2.0 equiv.) and stirred at room temperature for 5 h. Another portion of LiOH (2.4 mL, 2.39 mmol, 1.0 equiv.) was then added and the reaction mixture was stirred overnight. The reaction mixture was then quenched with a saturated solution of KHSO4 to pH < 5 and extracted with DCM to give 1.18 g (96% yield) of the desired product as the free acid. 1 H NMR (300MHz, DMSO-d6) δ3.90-3.52(m,1H)2.65(s,3H),2.13(tt,J=11.7,3.6Hz,1H),2.02-1.91(m,2H),1.66-1.45(m,4H),1.39(d,J=1.2Hz,11H).

[0152] Step 3: To a solution of 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (0.84 g, 0.7975 mmol, 1.0 equiv.) and (1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid (1.19 g, 4.61 mmol, 1.1 equiv.) in DMF (10 mL) was added DIPEA (2.2 mL, 12.56 mmol, 3.0 equiv.) and HATU (1.91 g, 5.02 mmol, 1.2 equiv.). The mixture was stirred at 25 °C for 1 h. UPLC showed the mass of the desired product. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography eluted with DCM:MeOH (0-10%) to give 1.18 g (64% yield) of the desired product. LCMS: ESI(+) [M+H] + =440.6. 1H NMR(300MHz,DMSO-d6)δ10.30(s,1H),9.78(s,1H),8.33(s,1H),8.11(s,1H),6.66(s,1H),2.82(d,3H), 2.65(s,3H),2.13(tt,J=11.7,3.6Hz,1H),2.02-1.91(m,2H),1.66-1.45(m,4H),1.39(d,J=1.2Hz,12H).

[0153] Step 4: To a suspension of tert-butyl N-methyl-N-[(1r,4r)-4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}cyclohexyl]carbamate (1.18 g, 2.68 mmol, 1.0 equiv.) in dry toluene (50 mL, 0.05 M) was added Lawesson's reagent (1.20 g, 2.95 mmol, 1.1 equiv.). The reaction mixture was stirred under reflux for 1.5 h, then quenched with water, washed with a saturated solution of NaHCO3, extracted with DCM, and concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH) to afford 0.7 g (60% yield) of the desired product as a white solid. LCMS: ESI(+) [M+H] + =438.6. 1 H NMR(300MHz,DMSO-d6)δ8.66(d,J=5.0Hz,1H),8.40(s,1H),6.83(s,1H),3.25-3.09(m,1H),2 .98(d,J=4.9Hz,3H),2.71(s,3H),2.21(d,J=10.3Hz,2H),1.69(d,J=7.4Hz,6H),1.41(s,9H).

[0154] Step 5: To a solution of tert-butyl N-methyl-N-[(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexyl]carbamate (0.7 g, 1.6 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.6 g, 2.23 mmol, 1.4 equiv), and Pd(dppf)Cl.CHCl (0.328 g, 0.4 mmol, 0.25 equiv) in anhydrous dioxane (30 mL) was added 2 M KCO (1.6 mL, 3.2 mmol, 2.0 equiv). The solution was degassed with argon for 2-3 minutes, then heated to 120 °C and stirred overnight. UPLC showed complete conversion of the starting material. The resulting solution was diluted with MeOH, filtered through a pad of Celite, and concentrated to dryness. The crude material was purified by chromatography eluting with DCM:MeOH (0-10%) to give 0.7% mp 100-1200°C. g (80% yield) of the desired product was obtained. LCMS: ESI(+) [M+H] + =546.1. 1 H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.2Hz,1H),8.74(d,J=2.2Hz,1H),8.71-8.58(m,2H),8.19(s,1H),7.88(d,J=4.8Hz,1H),7. 13(d,J=4.8Hz,1H),3.24-3.15(m,1H),3.09(d,J=4.9Hz,3H),2.71(s,3H),2.30-2.12(m,2H),1.76-1.53(m,6H),1.42(s,9H).

[0155] Step 6: tert-Butyl N-methyl-N-[(1r,4r)-4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]cyclohexyl]carbamate (0.67 g, 1.23 mmol, 1.0 equiv.) was dissolved in hexafluoro-2-propanol (4.0 mL, 30.0 equiv.) in a sealed cup reactor and placed in a microwave at 150 °C for 2 h. UPLC indicated complete deprotection of the starting material. The solvent was evaporated to dryness to give 0.54 g (99% yield) of the desired product as a yellow solid. LCMS: ESI(+) [M+H] + =444.97. 1 H NMR(300MHz,DMSO-d6)δ8.84(d,J=2.3Hz,1H),8.73(d,J=2.2Hz,1H),8.68-8.47(m,2H),8.18(s,1H),7.88(d,J=4.8Hz,1H),7.13(d,J=4.8Hz, 1H),3.20-3.10(m,1H),3.09(d,J=4.8Hz,3H),2.36-2.26(m,4H),2.20 -2.08(m,2H),2.07-1.96(m,2H),1.70-1.49(m,3H),1.33-1.11(m,2H).

[0156] Intermediate J: 7-[4-(methylamino)-5-{5-[4-(piperazin-1-yl)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0157] [ka]

[0158] The title compound was synthesized according to the same procedure as described for Intermediate T, except that tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. LCMS C 25 H 28N 10 S theoretical value: 500.2, measured value: m / z = 501.4 [M+H] + .

[0159] Intermediate K: 7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0160] [ka]

[0161] Step 1: To a solution of methyl 4,6-dichloronicotinate (95.0 g, 461 mmol, 1.00 equiv.) in ACN (1000 mL) was slowly added methylamine (288 g, 2.32 mol, 25% purity, 5.03 equiv.) at 0° C., and the mixture was stirred at 0° C. for 0.5 h and then at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure and ethyl acetate (500 mL) was added. * 3), and the combined organic layer was extracted with brine (500 mL * 2), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO, petroleum ether:ethyl acetate=20:1-10:1, R f =30). The desired product (39.0 g, 184 mmol, 40.0% yield) was obtained as a white solid. LCMS: m / z=201.1 (M+H). + .

[0162] Step 2: To a solution of methyl 6-chloro-4-(methylamino)nicotinate (39.0 g, 184 mmol, 1.00 equiv) in EtOH (300 mL) was added NHNH.H0 (86.6 g, 1.47 mol, 84.1 mL, 7.97 equiv) and the mixture was stirred at 80° C. for 3 h. The reaction mixture was concentrated and ethyl acetate (500 mL) was added. * The combined organic layer was extracted with brine (500 mL *The crude product was washed with 4), dried over NaSO, and concentrated to give the crude product. The crude product was triturated with petroleum ether / ethyl acetate = 15:1 (600 mL). The desired product (27.0 g, 120 mmol, 65.2% yield) was obtained as a white solid. LCMS: m / z = 201.2 (M+H). +

[0163] Step 3: To a solution of 6-chloro-4-(methylamino)nicotinohydrazide (8.00 g, 35.6 mmol, 1.00 equiv.) and 4-(((l-methyl)(l-oxidanyl)boraneyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (10.5 g, 39.2 mmol, 1.10 equiv.) in DMF (100 mL), DIEA (13.8 g, 107 mmol, 18.6 mL, 3.00 equiv.) and HATU (16.2 g, 42.8 mmol, 1.20 equiv.) were added at 25° C., and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was poured into water (100 mL) and ethyl acetate (100 mL) was added. * 3), and the combined organic layer was extracted with water (100 mL * 3), washed with brine (200 mL), dried, and concentrated to give the crude product. The crude was purified by preparative HPLC to give the desired product (15.0 g, 32.0 mmol, 89.7% yield) as a white solid. LCMS: m / z=452.4 (M+H). +

[0164] Step 4: To a solution of N'-(4-(((l-methyl)(l-oxideanil)boraneil)amino)bicyclo[2.2.2]octane-1-carbonyl)-6-chloro-4-(methylamino)nicotinohydrazide (15.0 g, 32.0 mmol, 1.00 equiv) in THF (300 mL), Lawesson's reagent (14.2 g, 35.2 mmol, 1.10 equiv) was added and the mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated to give the crude product. The crude was purified by preparative HPLC. The desired product (4.30 g, 9.33 mmol, 29.1% yield) was obtained as an off-white solid. LCMS: m / z = 450.3 (M+H). +

[0165] Step 5: To a solution of tert-butyl (4-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate (3.80 g, 8.44 mmol, 1.00 equiv), (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)boronic acid (2.37 g, 12.67 mmol, 1.50 equiv), and KPO (2 M, 8.44 mL, 2.00 equiv) in DME (4.00 mL) was added Pd(dppf)Cl·CHCl (689 mg, 844 μmol, 0.10 equiv) under N. The resulting mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered, and the filtrate was diluted with DCM (80.0 mL). * The residue was extracted with HCl / dioxane (4 M, 4.00 mL, 4.53 equiv.) in dioxane (20 mL) at 25° C. for 12 hours. The mixture was concentrated in vacuo. The residue in EtOAc (20.0 mL) was heated to 90° C. for 30 min and filtered three times to give 7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.67 g, 3.22 mmol, 33.7% yield, HCl) as a brown solid. LCMS: m / z=557.2

[0166] Intermediate L: 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0167] [ka]

[0168] Step 1: A stirred suspension of 2,5-dibromo-1,3,4-thiadiazole (1.05 g, 4.31 mmol, 1.0 equiv), 8-Boc-3,8-diaza-bicyclo[3.2.1]octane (1.005 g, 4.73 mmol, 1.1 equiv), and N,N-diisopropylethylamine (1.125 mL, 6.46 mmol, 1.5 equiv) in anhydrous dioxane (21.53 mL, 0.2 M) was heated at 120° C. for 1 h. The reaction mixture was diluted with water, extracted with DCM, and the organic phase was concentrated onto silica gel. The crude material was purified by flash chromatography using an EtOAc / hexane gradient to give 7-[5-bromo-4-(methylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow oil (0.819 g, 2.18 mmol, 71%). LCMS: ESI(+) [M+H] + =337.3. 1 H NMR (300MHz, CDCl3) δ4.37(s,2H),3.72-3.26(m,4H),2.03(m,2H),1.82(m,2H),1.50(d,J=0.8Hz,9H).

[0169] Step 2: 7-[5-Bromo-4-(methylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.5 g, 4.57 mmol, 1.0 equiv.) was dissolved in dioxane (25 mL, 0.18 M) in a pressure reactor, followed by the addition of bis(pinacolato)diboron (1.39 g, 5.49 mmol, 1.2 equiv.) and KOAc (1.39 g, 14.17 mmol, 3.1 equiv.). The solution was sparged with argon for several minutes, and Pd(dppf)Cl·DCM (0.373 g, 0.46 mmol, 0.1 equiv.) was added, followed by repeated sparging. The reaction mixture was then transferred to a preheated oil bath and stirred at 90 °C overnight. The reaction mixture was filtered through a pad of Celite and evaporated to dryness. The crude material was used in the next step without further purification.

[0170] Step 3: To a solution of 7-[4-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.58 g, 1.55 mmol, 1.0 equiv), tert-butyl 3-(5-bromo-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.638 g, 1.70 mmol, 1.1 equiv) in dioxane (40 mL, 0.04 M) was added CsCO (1.26 g, 3.86 mmol, 2.5 equiv) and Xantphos (0.358 g, 0.62 mmol, 0.4 equiv). The reaction was sparged with argon for several minutes, followed by the addition of Pd(OAc)2 (0.069 g, 0.31 mmol, 0.2 equiv). The solution was degassed with argon for 2-3 minutes and then stirred at 120 °C overnight. The reaction mixture was filtered through a pad of Celite and evaporated to dryness. The crude material was purified by FC eluting with DCM / MeOH (0-10%). The main fraction was repurified by pTLC eluting with DCM / MeOH (0-10%) and finally triturated with Et2O to give 0.190 g (23% yield) of the desired product. LCMS: ESI (+) [M+H] + =544.77. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.3Hz,1H),8.51-8.43(m,2H),8.14(s,1H),7.85(d,J=4.8Hz,1H),7.12(d,J=4.8 Hz,1H),4.28(s,2H),3.67(d,J=11.8Hz,2H),3.37(d,2H),3.06(d,J=4.9Hz,3H),1.91(d,J=6.3Hz,2H),1.75(d,J=7.4Hz,2H),1.44(s,9H).

[0171] Step 4: tert-Butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.120 g, 0.22 mmol, 1.0 equiv.) was added to 1,1,1,3,3,3-hexafluoro-2-propanol (0.7 mL, 30 equiv.) in a pressure vessel and heated in a microwave at 150 °C for 2.5 h. The solvent was evaporated to dryness and the residue was purified with EtO. Trituration gave 0.080 g (82% yield) of the title compound. LCMS: ESI(+) [M+H] + =444.05. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.3Hz,1H),8.72(d,J=2.2Hz,1H),8.52-8.44(m,2H),8.13(s,1H),7.85(d, J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),3.61-3.46(m,4H),3.29(s,3H),3.06(m,3H),1.70(dd,J=9.8,6.7Hz,4H).

[0172] Intermediate M: 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]cyclohexane-1-carboxylic acid hydrochloride.

[0173] [ka]

[0174] Step 1: To a solution of 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (10.0 g, 49.84 mmol, 1.0 equiv.) and 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (11.63 g, 54.83 mmol, 1.1 equiv.) in DMF (175 mL, 0.285 M) was added DIPEA (149.53 mmol, 26 mL, 3.0 equiv.) and HATU (22.74 g, 59.81 mmol, 1.2 equiv.). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with a water / ice mixture (600 mL) and extracted with EtOAc. The combined organic layer was washed with aqueous NaHCO3, aqueous KHSO4, water, brine, and dried over Na2SO4. After evaporation of the volatiles, the crude was purified by column chromatography (DCM / MeOH) to give methyl 4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}bicyclo-[2.2.2]octane-1-carboxylate as a white solid (15.6 g, 79% yield). LCMS: ESI(+) [M+H] + =395.62. 1 H NMR(300MHz,DMSO-d6),δ:10.23(1H,s),9.48(1H,s),8.35(1H,s),8.14(1 H,br.q,J5.1),6.66(1H,s),3.59(3H,s),2.82(3H,d,J4.9),1.76(12H,m).

[0175] Step 2: Methyl 4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}bicyclo-[2.2.2]octane-1-carboxylate (5.0 g, 12.66 mmol, 1 equiv.) was dissolved in THF (250 mL, 0.05 M) under argon. The solution was warmed to 40 °C, and P2S5 (4.22 g, 18.99 mmol, 1.5 equiv.) was added portionwise with vigorous stirring. The resulting suspension was then refluxed. The mixture was stirred under reduced pressure for 2 hours (controlled by UPLC). After completion, the volatiles were evaporated. The residue was dissolved in DCM and washed with saturated K2CO3 solution. The aqueous layer was removed in a separatory funnel, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by FC (DCM / EA) to give 4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexane-1-carboxylate (2.66 g, 53% yield). LCMS: ESI(+) [M+H] + =393.4. 1 H NMR (300MHz, DMSO-d6), δ:8.66(1H,br.q,J5.2),8.38(1H,s),6.82(1H,s),3.61(3H,s),2.97(3H,d,J4.9),2.05-1.94(6H,m),1.94-1.82(6H,m).

[0176] Step 3: To an argon-flushed flask containing methyl 4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexane-1-carboxylate (4.04 g, 10.9 mmol, 1.0 equiv.), cesium acetate (5.2 g, 27.2 mmol, 2.5 equiv.), and Pd(dppf)Cl·DCM (1.74 g, 2.2 mmol, 0.2 equiv.) in THF (218 mL, 0.05 M) was added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (4.401 g, 16.35 mmol, 1.5 equiv.). The mixture was stirred at 85 °C overnight. The mixture was filtered through a pad of Celite, concentrated in vacuo, redissolved in dichloromethane, and deposited onto silica gel. The resulting solid was purified by flash chromatography (0-10% gradient of acetonitrile in DCM) to give methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]cyclohexane-1-carboxylate as a yellow crystalline solid (2.9 g, 56% yield). LCMS: ESI(+) [M+H] + =474.60.1 H NMR(300MHz,DMSO-d6),δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.62 (d,J=6.0Hz,2H),8.22-8.12(m,1H),7.87(d,J=4.8Hz,1H),7.11(d,J=4.8Hz, 1H),3.62(s,3H),3.19(s,1H),3.08(d,J=4.9Hz,3H),2.42(d,J=11.7Hz,1H), 2.19(d,J=10.3Hz,2H),2.03(d,J=10.7Hz,2H),1.59(q,J=12.3,11.2Hz,4H).

[0177] Step 4: To a solution of methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]cyclohexane-1-carboxylate (2.9 g, 6.1 mmol, 1.0 equiv.) in dry pyridine (61.2 mL, 0.1 M), lithium iodide (8.3 g, 61.2 mmol, 10 equiv.) was added, and the resulting mixture was stirred at 150 °C until completion (24-48 h using UPLC control). The resulting mixture was then acidified with an equimolar amount of dilute HCl. The resulting solid was purified by column chromatography (0-20% gradient of 2-propanol in DCM) to afford the target compound as a yellow solid (3.1 g, 95% yield). LCMS: ESI(+) [M+H] + =460.23. 1 H NMR(300MHz,DMSO-d6),δ:12.17(s,1H),9.59(d,J=4.2Hz,1H),8.99(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.69(s,1H),8.15(d,J=4.9Hz,1H),7 .95(s,1H),7.24(d,J=5.0Hz,1H),3.32(m,1H),3.22(d,J=4.8Hz,3H),2. 40-2.28(m,1H),2.21(d,J=11.8Hz,2H),2.04(s,2H),1.72-1.46(m,4H).

[0178] Intermediate N: 7-[4-(methylamino)-5-{5-[(1r,4r)-4-formylcyclohexyl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl]pyrro b) [1,2-b]pyridazine-3-carbonitrile.

[0179] [ka]

[0180] Step 1: To a solution of methyl 4,6-dichloronicotinate (99.0 g, 481 mmol, 1.0 equiv.) in acetonitrile (990 mL, 0.49 M), methylamine 40 wt.% (208 mL, 2403 mmol, 5.0 equiv.) was slowly added at -5 °C. The mixture was stirred at 0 °C for 30 min and then at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / EtOAc, 0-50%) to give methyl 6-chloro-4-(methylamino)pyridine-3-carboxylate as a white solid (65.3 g, 68% yield). LCMS: ESI(+) [M+H] + =202.2. 1 H NMR (300MHz, DMSO-d6)δ:8.50(s,1H),8.04(d,J=5.5Hz,1H),6.74(s,1H),3.83(3H,s),2.88(d,J=5.0Hz,3H).

[0181] Step 2: To a solution of methyl 6-chloro-4-(methylamino)pyridine-3-carboxylate (43 g, 0.21 mol, 1 eq.) in EtOH (358 mL, 0.6 M), hydrazine hydrate (129 mL, 1.68 mol, 8.0 eq.) was added, and the resulting mixture was stirred at 80 °C for 4 h (UPLC control applied). The reaction mixture was then cooled to room temperature and extracted multiple times with DCM. The combined organic layers were dried over NaSO, and the solvent was concentrated in vacuo to give 6-chloro-4-(methylamino)pyridine-3-carbohydrazide as a white crystalline solid (34.4 g, 79% yield). LCMS: ESI(+) [M+H] + =200.95. 1 H NMR (300MHz, DMSO-d6) δ: 9.81 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 6.62 (s, 1H), 4.46 (s, 2H), 2.82 (d, J = 5.0Hz, 3H).

[0182] Step 3: To a solution of 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (12.0 g, 59.81 mmol, 1.0 equiv.) and monomethyl trans-1,4-cyclohexanedicarboxylate (12.25 g, 65.79 mmol, 1.1 equiv.) in DMF (150 mL) was added DIPEA (179.43 mmol, 32 mL, 3.0 equiv.) and HATU (27.29 g, 71.77 mmol, 1.2 equiv.). The mixture was stirred at 25° C. for 1 h, then quenched with water, brine was added, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue The product was purified by column chromatography eluting with DCM / MeOH (0-10%) to give methyl (1r,4r)-4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}cyclohexane-1-carboxylate (15.5 g, 70% yield). LCMS: ESI(+) [M+H] + =367.46. 1H NMR(300MHz,DMSO-d6)δ:10.31(s,1H),9.81(s,1H),8.34(s,1H),8.12(q,J=4.9Hz,1H),6.66(s,1H),3.60(s,3H), 3.33(s,2H),2.82(d,J=4.9Hz,3H),2.40-2.16(m,2H),2.02-1.91(m,2H),1.82(t,J=7.2Hz,2H),1.55-1.25(m,4H).

[0183] Step 4: To a solution of methyl (1r,4r)-4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}cyclohexane-1-carboxylate (11.35 g, 30.77 mmol, 1 equiv) in anhydrous THF (1000 mL, 0.03 M) was added phosphorus pentasulfide (8.9 g, 40.01 mmol, 1.3 equiv) at 20 °C. The resulting mixture was stirred at 50 °C for 3 h. The reaction was filtered, washed with THF, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / EA) to give methyl (1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexane-1-carboxylate (4.46 g, 40%). LCMS: ESI(+)[M+H] + =367.48. 1 H NMR(300MHz,DMSO-d6)δ:8.65(d,J=5.2Hz,1H),8.39(s,1H),6.82(s,1H),3.62(s,3H),3.21(td,J= 11.4Hz, 3.5Hz, 1H), 2.98 (d, J=4.9Hz, 3H), 2.48-2.37 (m, 1H), 2.22-1.96 (m, 4H), 1.72-1.45 (m, 4H).

[0184] Step 5: A solution of methyl (1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexane-1-carboxylate (4.26 g, 11.61 mmol, 1 equiv.) in anhydrous THF (180.0 mL, 0.06 M) was cooled to −15 °C under an argon atmosphere and treated with DIBAL-H (35 mL of a 1.0 M solution in THF, 34.8 mmol, 3.0 equiv.). After 30 min, the cooling bath was removed, and the mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the reaction was quenched by adding MeOH (30 mL) and stirred vigorously for 20 min, followed by the addition of a saturated aqueous solution of Rochelle's salt. The resulting mixture was extracted with DCM. The combined organic layers were washed with a dilute solution of KHSO4, water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / ACN) to give [(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexyl]methanol (3.0 g, 8.85 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.19 g, 81% yield). LCMS: ESI(+) [M+H] + =339.48. 1 H NMR(300MHz,DMSO-d6)δ:8.66(d,J=4.6Hz,1H),8.38(s,1H),6.82(s,1H),4.46(t,J=5.3Hz,1H),3.26(t,J=5.8Hz,2H),3.14( tt,J=11.9Hz,3.6Hz,1H),2.97(d,J=4.9Hz,3H),2.22-2.10(m,2H),1.92-1.80(m,2H),1.64-1.36(m,3H),1.26-1.00(m,2H).

[0185] Step 6: [(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazolium]-4-[ ... To a solution of [[[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl}cyclohexyl)methanol] (3.0 g, 8.85 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.4 g, 12.4 mmol, 1.4 equiv.), and Pd(dppf)Cl₂·CHCl₂ (1.82 g, 2.21 mmol, 0.25 equiv.), 2 M aqueous KCO₂ solution (9 mL, 17.71 mmol, 2.0 equiv.) was added. The mixture was degassed with argon for 30 min and then stirred at 120 °C for 25 h. The reaction was diluted with DCM, filtered through a pad of Celite, washed with DCM / MeOH (1:1), and concentrated in vacuo. The residue was purified twice by column chromatography (DCM / ACN and DCM / IPA, respectively) to give 7-[4-(methylamino)-5-{5-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.35 g, 60% yield). LCMS: ESI(+) [M+H] + =446.38. 1 H NMR(300MHz,DMSO-d6)δ:8.84(d,J=2.2Hz,1H),8.73(d,J=2.2Hz,1H),8.64(d, J=9.7Hz,2H),8.17(s,1H),7.87(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),4.47( t,J=5.3Hz,1H),3.27(t,J=5.8Hz,2H),3.22-3.11(m,1H),3.09(d,J=4.9Hz,3H ),2.23-2.13(m,2H),1.93-1.83(m,2H),1.66-1.39(m,3H),1.26-1.00(m,4H).

[0186] Step 7: To a solution of 7-[4-(methylamino)-5-{5-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.35 g, 5.27 mmol, 1 equiv.) in DCM (1.3 L, 0.004 M) was added Dess-Martin periodinane (2.91 g, 6.86 mmol, 1.3 equiv.). The mixture was stirred at room temperature overnight. The reaction was quenched with 20% aqueous NaSO and saturated aqueous NaHCO and stirred until the aqueous layer became clear. The latter was extracted with DCM. The combined organic layers were dried over NaSO and concentrated in vacuo. The residue was purified by trituration with DCM / Et2O (1:1) to give the title compound (1.83 g, 78% yield). LCMS: ESI(+) [M+H] + =444.22. 1 H NMR(300MHz,DMSO-d6)δ:9.63(br.d,J=1.1Hz,1H),8.84(d,J=2.3Hz,1H),8.74(d,J=2.2Hz, 1H),8.66(s,1H),8.65(q,J=2.7Hz,1H),8.17(s,1H),7.88(d,J=4.8Hz,1H),7.12(d,J=4.8Hz ,1H),3.19(ddt,J=11.7Hz,7.0Hz,3.6Hz,1H),3.09(d,J=4.9Hz,3H),2.41(ddt,J=12.2Hz,7. 3Hz, 3.7Hz, 1H), 2.29-2.18 (m, 2H), 2.14-2.02 (m, 2H), 1.75-1.55 (m, 2H), 1.51-1.31 (m, 2H).

[0187] Intermediate O: 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]cyclohexane-1-carboxylic acid.

[0188] [ka]

[0189] Step 1: To an argon-flushed flask containing methyl 4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexane-1-carboxylate (4 g, 10.9 mmol, 1 equiv.), CsOAc (5.3 g, 27.3 mmol, 2.5 equiv.), and Pd(dppf)Cl·DCM (1.74 g, 2.18 mmol, 0.2 equiv.) in THF (218 mL, 0.05 M) was added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (4.4 g, 16.35 mmol, 1.5 equiv.). The mixture was stirred at 85 °C overnight. The reaction was filtered, concentrated in vacuo, dissolved in DCM, and adsorbed onto silica gel. The solid was purified by flash chromatography (0-10% ACN in DCM) to give the desired compound as a yellow crystalline solid (2.9 g, 56% yield). LCMS: ESI(+) [M+H] + =474.60. 1 H NMR(300MHz,DMSO-d6),δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.62 (d,J=6.0Hz,2H),8.22-8.12(m,1H),7.87(d,J=4.8Hz,1H),7.11(d,J=4.8Hz, 1H),3.62(s,3H),3.19(s,1H),3.08(d,J=4.9Hz,3H),2.42(d,J=11.7Hz,1H), 2.19(d,J=10.3Hz,2H),2.03(d,J=10.7Hz,2H),1.59(q,J=12.3,11.2Hz,4H).

[0190] Step 2: To a solution of methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]cyclohexane-1-carboxylate (2.9 g, 6.12 mmol, 1 equiv.) in dry pyridine (61 mL, 0.1 M), lithium iodide (8.27 g, 61.18 mmol, 10 equiv.) was added, and the resulting mixture was stirred at 150 °C for 24 h. The resulting mixture was acidified with an equimolar amount of dilute HCl. The resulting solid was filtered off and purified by flash chromatography (0-20% 2-propanol in DCM) to give the desired compound as a yellow solid (2.5 g, 89% yield). LCMS: ESI(+) [M+H] + =460.23. 1 H NMR(300MHz,DMSO-d6),δ:12.17(s,1H),9.59(d,J=4.2Hz,1H),8.99(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.69(s,1H),8.15(d,J=4.9Hz,1H),7 .95(s,1H),7.24(d,J=5.0Hz,1H),3.32(m,1H),3.22(d,J=4.8Hz,3H),2. 40-2.28(m,1H),2.21(d,J=11.8Hz,2H),2.04(s,2H),1.72-1.46(m,4H).

[0191] Intermediate P: 7-[4-(methylamino)-5-{5-[(1r,4r)-4-(ethylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0192] [ka]

[0193] Step 1: To a solution of methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (2.0 g, 7.8 mmol, 1.0 equiv.) in DMF (25 mL, 0.46 M) cooled to 0 °C, NaH (0.357 g, 9.32 mmol, 1.2 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min. Ethyl iodide (0.937 mL, 11.66 mmol, 1.5 equiv.) was then added, and the reaction mixture was stirred at room temperature overnight. DMF was then azeotropically removed by coevaporation with PhMe (3 × 100 mL). 50 mL of a saturated aqueous solution of NH Cl was added to the remaining solid. The resulting mixture was transferred to a separatory funnel and extracted with Et O (4 × 50 mL). The combined organic layers were dried over Na SO and concentrated in vacuo. The crude material was purified by column chromatography (hexane / EtOAc, gradient 0% to 20%) to give methyl (1r,4r)-4-{[(tert-butoxy)carbonyl](ethyl)amino}cyclohexane-1-carboxylate as a yellowish viscous oil (1.883 g, 85% yield). 1 H NMR(300MHz,DMSO-d6)δ3.63(s,3H),3.07(q,J=7.1Hz,2H),2.26(t,J=11.9Hz,1H),1.94 (d,J=12.5Hz,2H),1.55(d,J=27.9Hz,4H),1.39(d,J=1.7Hz,12H),1.02(t,J=6.8Hz,3H).

[0194] Step 2: To methyl (1r,4r)-4-{[(tert-butoxy)carbonyl](ethyl)amino}cyclohexane-1-carboxylate (1.88 g, 6.6 mmol, 1.0 equiv) in a mixture of THF (15 mL, 0.44 M) and water (3.0 mL, 2.41 M) was added LiOH *HO (0.57 g, 13.2 mmol, 2.0 equiv) was added, and the reaction mixture was stirred at room temperature overnight. After NMR showed complete substrate consumption, the THF was then removed in vacuo, and the resulting aqueous solution was acidified to pH 5 with a 10 wt% solution of NaHSO. The resulting suspension was then extracted with EtOAc (4 × 25 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give (1r,4r)-4-{[(tert-butoxy)carbonyl](ethyl)amino}cyclohexane-1-carboxylic acid as a white solid (1.566 g, 87% yield). 1 H NMR(300MHz,DMSO-d6)δ12.08(s,1H),3.07(d,J=7.3Hz,2H),2.13(tt,J=11.9,3.4Hz,1H),1.93(dt,J=9.2, 2.8Hz,2H),1.52(dd,J=28.7,16.5Hz,4H),1.39(s,9H),1.33(dd,J=12.4,3.8Hz,1H),1.02(t,J=6.8Hz,3H) .

[0195] Step 3: To a solution of (1r,4r)-4-{[(tert-butoxy)carbonyl](ethyl)amino}cyclohexane-1-carboxylic acid (1.57 g, 5.77 mmol, 1.00 equiv) in anhydrous DMF (15 mL, 0.38 M) was added DIPEA (3.0 mL, 17.3 mmol, 3.00 equiv) and HATU (3.29 g, 8.65 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 30 min, and 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (1.216 g, 6.06 mmol, 1.05 equiv) was added. After 2 h at room temperature, the reaction was quenched with brine and extracted with EtOAc (5 × 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The resulting crude material was purified by column chromatography (DCM / MeOH, gradient 0-3%) to give the desired product as a light brown solid (1.87 g, 71% yield). LCMS: ESI(+) [M+H] + =454.4. 1H NMR(300MHz,DMSO-d6)δ10.31(s,1H),9.82(s,1H),8.35(s,1H),8.12(d,J=5.3Hz,1H),6.67(s,1H),3.13-3.06(m,2H),2.83( d,J=4.9Hz,3H),2.23(dd,J=14.7,4.0Hz,1H),1.85(d,J=11.3Hz,2H),1.69-1.46(m,5H),1.41(s,9H),1.04(t,J=6.8Hz,3H).

[0196] Step 4: To a solution of tert-butyl N-ethyl-N-[(1r,4r)-4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}cyclohexyl]carbamate (1.87 g, 4.11 mmol, 1.0 equiv) in anhydrous THF (100 mL, 0.04 M) was added Lawesson's reagent (1.83 g, 4.52 mmol, 1.1 equiv). The reaction mixture was stirred at 90 °C for 2 h. The volatiles were removed in vacuo, and the residue was dissolved in 50 mL of DCM and washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (3 x 50 mL). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by dual column chromatography (DCM / MeOH, gradient 0-4% and hexane / EtOAc, gradient 0-40%) to give tert-butyl N-ethyl-N-[(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexyl]carbamate as a white foamy solid (0.794 g, 43% yield). LCMS: ESI(+) [M+H] + =452.5. 1 H NMR(300MHz,DMSO-d6)δ8.66(d,J=5.9Hz,1H),8.39(d,J=1.6Hz,1H),6.82(d,J=1.7Hz,1H),3.16(t,J=12.0Hz, 3H),2.98(d,J=4.9Hz,3H),2.24-2.14(m,2H),1.69(d,J=20.3Hz,7H),1.41(d,J=2.0Hz,9H),1.12-1.01(m,3H).

[0197] Step 5: tert-Butyl N-ethyl-N-[(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}cyclohexyl]carbamate (0.794 g, 1.76 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2)-pyridin-3-yl-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate in anhydrous dioxane (25 mL, 0.07 M) A suspension of -dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.662 g, 2.46 mmol, 1.4 equiv.), Pd(dppf)Cl2·CHCl2 (0.36 g, 0.44 mmol, 0.25 equiv.), and KCO3 (0.485 g, 3.5 mmol, 2.0 equiv.) was degassed with argon for 2–3 min and stirred at 120 °C overnight. After complete conversion of the starting material, the reaction was diluted with MeOH, filtered through a pad of Celite, and concentrated in vacuo. The crude product was purified by FC (DCM / ACN, gradient 0–40%) to afford tert-butyl N-ethyl-N-[(1r,4r)-4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methyl 3-methylpropional]-4-yl]-4-methylpropional]-4-methylpropional. Amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]cyclohexyl]carbamate was obtained as a yellow solid (0.676 g, 69% yield). LCMS: ESI(+) [M+H] + =559.85. 1 H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.2Hz,1H),8.74(d,J=2.3Hz,1H),8.67(s,1H),8.63(d,J=5.0Hz,1H),8.19(s,1H),7.88(d,J=4.8Hz,1H) ,7.13(d,J=4.8Hz,1H),3.26-3.12(m,3H),3.09(d,J=4.9Hz,3H),2.21(d,J=11.2Hz,2H),1.83-1.57(m,6H),1.42(s,9H),1.12-1.02(m,3H).

[0198] Step 6: Tert-butyl N-ethyl-N-[(1r,4r)-4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]cyclohexyl]carbamate (0.676 g, 1.21 mmol, 1.0 equiv.) was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (3.185 mL, 25 equiv.) and stirred at 150 °C for 8 h. After complete consumption of the starting material, the reaction mixture was coevaporated several times with DCM to remove traces of HFIP. The crude product was purified by column chromatography (DCM / MeOH, gradient 0-30%) to afford the title compound as a dark yellow solid (0.350 g, 63% yield). LCMS: ESI(+) [M+H] + =459.03. 1 H NMR(300MHz,DMSO-d6)δ8.84(s,1H),8.74(s,1H),8.65(s,2H),8.17(d,J=3.1Hz,1 H),7.87(d,J=4.8Hz,1H),7.12(d,J=4.7Hz,1H),4.10(s,1H),3.17(s,2H),3.09(d, J=4.7Hz,3H),2.71-2.56(m,3H),2.16(d,J=12.8Hz,2H),2.04(t,J=11.7Hz,2H),1 .60(q,J=12.4Hz,3H),1.32-1.13(m,5H),1.04(t,J=6.8Hz,3H),0.82-0.71(m,1H).

[0199] Intermediate Q: 7-[5-(5-{3,9-diazaspiro[5.5]undecan-3-yl}-1,3,4-thiadiazol-2-yl)-4-(oxan-4-ylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0200] [ka]

[0201] Synthesized according to the same procedure as described for Intermediate T, except that tert-butyl 3,9-diazaspiro[2.5]undecane-3-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[5.5]octane-4-carboxylate. LCMS C 29 H 33 N9OS theoretical value: 555.3, measured value: m / z = 556.3 [M+H] + .

[0202] Intermediate R: 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)-4-[(propan-2-yl)amino]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0203] [ka]

[0204] The title compound was synthesized according to the same procedure as described for intermediate L, except that 7-{5-bromo-4-[(propan-2-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile was used as the starting material instead of 7-{5-bromo-4-[(methylamino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile. LCMS: ESI(+) [M+H] + =472.20. 1 H NMR(300MHz,DMSO-d6)δ:8.82(d,J=2.2Hz,1H),8.71(d,J=2.2Hz,1H),8.56(d,J=7.1Hz,1H),8.46(s,1H),8.18(s,1H),7.83(d,J=4.8Hz,1 H),7.11(d,J=4.8Hz,1H),3.91(h,J=6.5Hz,1H),3.60-3.44(m,4H),3.32-3.24(m,3H),1.69(dd,J=10.0,6.9Hz,4H),1.34(d,J=6.3Hz,6H).

[0205] Intermediate S: 7-(4-((4,4-difluorocyclohexyl)amino)-5-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0206] [ka]

[0207] Step 1: 2-Bromo-N-(4,4-difluorocyclohexyl)pyridin-4-amine (6.00 g, 20.6 mmol, 1.00 equiv.) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrroloamine in DME (60.0 mL) To a solution of [1,2-b]pyridazine-3-carbonitrile (6.66 g, 24.7 mmol, 1.20 equiv.) was added KPO (2.00 M, 20.6 mL, 2.00 equiv.) and Pd(dppf)Cl CHCl (1.68 g, 2.06 mmol, 0.10 equiv.) under N, and the mixture was stirred at 100 °C for 2 h under N. The reaction mixture was poured into water (50.0 mL), then filtered and diluted with ethyl acetate (100 mL). * 4), the filter cake (4.0 g) was collected and concentrated under vacuum. The filtrate was diluted with ethyl acetate (100 mL * The residue (2.00 g) was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to dichloromethane / methanol = 20 / 1, R f =0.20). The product isolated by column chromatography was combined with the filtered product to give the desired product (5.00 g, 14.1 mmol, 68.6% yield) as a yellow solid. LCMS: m / z=354.3 (M+H). + .

[0208] Step 2: To a solution of 7-(4-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.50 g, 15.5 mmol, 1.00 equiv) in MeCN (230 mL) and DCM (230 mL) was added a solution of NBS (2.49 g, 14.0 mmol, 0.90 equiv) in MeCN (45.0 mL) and DCM (45.0 mL) at 0° C., and the mixture was stirred at 0° C. for 0.5 h. The reaction mixture was concentrated in vacuo. The crude product was triturated with ethyl acetate (20.0 mL) at 25° C. for 30 min to give the desired product (6.00 g, 13.8 mmol, 89.1% yield) as a yellow solid, which was confirmed by LCMS. LCMS: m / z=432.2 (M+H). + .

[0209] Step 3: To a solution of 7-(5-bromo-4-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (480 mg, 1.11 mmol, 1.00 equiv) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (563 mg, 2.22 mmol, 2.00 equiv) in dioxane (10.0 mL) and DMF (5.00 mL) was added KOAc (326 mg, 3.33 mmol, 3.00 equiv) and Pd(PPh)Cl (116 mg, 166 μmol, 0.15 equiv) under N, and the mixture was then stirred at 80° C. for 2 h. The crude material was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions) and then concentrated by lyophilization to give the desired product (1.40 g, 2.87 mmol, 23.5% yield) as a yellow solid. LCMS: m / z=398.2 (M+H). + .

[0210] Step 4: To a solution of (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4,4-difluorocyclohexyl)amino)pyridin-3-yl)boronic acid (700 mg, 1.43 mmol, 1.00 equiv, FA) and tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (525 mg, 1.51 mmol, 1.05 equiv) in DME (15.0 mL) was added XPhos Pd G3 (121 mg, 143 μmol, 0.10 equiv) and K3PO4 (2.00 M, 1.79 mL, 2.50 equiv) under N2. The mixture was stirred at 100 °C under N2 for 1 h. The reaction was poured into water (20.0 mL), then filtered and diluted with ethyl acetate (10.0 mL * 4), and the filtrate was washed with ethyl acetate (20.0 mL * 3) and then concentrated under vacuum to give a residue. The residue was then characterized by HPLC, purified by preparative HPLC, and concentrated by lyophilization to give the desired product (600 mg, 965 μmol, 33.6% yield) as a yellow solid. LCMS: m / z=622.2 (M+H). + .

[0211] Step 5: tert-Butyl 4-(5-(6-(3-cyclohexyl)methyl)-2-methyl ... To a solution of anopyrrolo[1,2-b]pyridazin-7-yl)-4-((4,4-difluorocyclohexyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (600 mg, 965 μmol, 1.00 equiv.) was added HCl / EtOAc (4 M, 2.57 mL, 10.6 equiv.), and the mixture was stirred for 15 minutes at 25° C. The resulting mixture was concentrated in vacuo. The crude product was triturated with ethyl acetate (1.00 mL) at 25° C. for 15 minutes, then filtered, and the filter cake was concentrated in vacuo to give 7-(4-((4,4-difluorocyclohexyl)amino)-5-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (310 mg, 511 μmol, 52.9% yield, HCl) as a yellow solid, which was confirmed by LCMS. LCMS: m / z=522.1 (M+H). + . 1 H NMR:400MHz,DMSO-d6.δ9.78(d,J=7.2Hz,1H),9.57(s,2H),9.01(d,J=2.0Hz,1H),8.92(d,J=2.0Hz,1H),8.55(s,1H),8.30(d,J=5.2 Hz,1H),8.16(s,1H),7.26(d,J=4.8Hz,1H),4.24-4.17(m,2H),3.72-3.69(m,5H),3.23(s,2H),2.17-2.10(m,6H),1.76-1.73(m,2H).

[0212] Intermediate T: 7-[5-(5-{4,7-diazaspiro[2.5]octan-7-yl}-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0213] [ka]

[0214] Step 1: Dibromothiadiazole (500 mg, 2.05 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (435 mg, 1 equiv.) were dissolved in DIEA (0.6 mL, 1.75 equiv.) and dioxane (0.15 M) and then heated to 110 °C in a sealed vial. The reaction was stirred for 1.5 h, then cooled and concentrated onto silica gel. Silica gel column chromatography (0-5% methanol in DCM) afforded the desired product (0.105 g, 14%). LCMS C 13 H 19 N4BrO2S Theoretical value: 374.0, Measured value: m / z = 320.9 [M-tert-butyl] + .

[0215] Step 2: 6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(isopropylamino)pyridin-3-ylboronic acid (90 mg, 0.28 mmol), cesium carbonate (0.2 g, 2.2 equiv.), Xantphos (0.06 g, 0.4 equiv.), palladium acetate (13 mg, 0.2 equiv.), and tert-butyl 7-(5-bromo-1,3,4-thiadiazol-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (105 mg, 1 equiv.) were combined in a microwave vial, followed by the addition of dioxane (8 mL). The reaction mixture was then purged with nitrogen for 1 minute and stirred at 145 °C in a microwave reactor for 30 minutes. The reaction was then filtered through Celite and concentrated onto silica gel. Chromatography (0-10% methanol in DCM) afforded the desired intermediate. The material was dissolved in DCM:TFA (5:1 ratio of DCM to TFA, 0.1 M) and stirred at room temperature for 1 hour. It was stirred for 3 hours, and the reaction was concentrated and purified by reverse-phase chromatography on a C18 column (0-100% ACN in water, 0.1% TFA), followed by overnight lyophilization to give the desired product (28 mg, 21% yield).

[0216] LCMS C 24 H 25 N9S theoretical value: 471.2, measured value: m / z = 472.3 [M+H] + .

[0217] Intermediate U: [5-(5-{4-formylbicyclo[2.2.2]octan-1-yl}-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0218] [ka]

[0219] Step 1: A solution of methyl 4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}bicyclo[2.2.2]octane-1-carboxylate (3.8 g, 9.67 mmol, 1 equiv.) in anhydrous THF (270 mL, 0.036 M) was cooled to −15 °C under an argon atmosphere and treated with DIBAL-H (29 mL, 1.0 M solution in THF, 29.02 mmol, 3 equiv.). After 30 min, the cooling bath was removed, and the reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was then quenched by the addition of MeOH (30 mL) and stirred vigorously for 20 min, followed by the addition of a saturated aqueous solution of Rochelle's salt. The resulting mixture was extracted with DCM, and the combined organic layers were washed with saturated NH₄Cl solution, dried over Na₂SO₄, and concentrated under reduced pressure. The crude material was purified by column chromatography (eluting with DCM / ACN) to give 3.25 g of (4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)methanol (92% yield). LCMS: ESI(+) [M+H] + =365.46. 1 H NMR(300MHz,DMSO-d6)δ:8.68(q,J=5.2Hz,1H),8.38(s,1H),6.81(s,1H),4.46(t,J=5.4H) z,1H),3.10(d,J=5.0Hz,2H),2.97(d,J=4.9Hz,3H),2.00-1.89(m,6H),1.56-1.45(m,6H).

[0220] Step 2: (4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)methanol (1.8 g, 4.93 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.59 g, 5.92 mmol, 1.2 equiv.) and Pd(dppf)Cl CHCl (1.01 g, To a solution of 7-(5-{5-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-1,3,4-thiadiazol-2-yl}-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.46 g, 63% yield) was added 2 M aqueous K2CO3 (5 mL, 9.87 mmol, 2.0 equiv). The reaction mixture was degassed with argon for 30 min and then stirred at 120 °C for 25 h. The reaction mixture was diluted with DCM, filtered through a pad of Celite, washed with DCM / MeOH (1:1), and concentrated under reduced pressure. The crude product was purified twice by column chromatography (DCM / acetone and DCM / IPA) to give 7-(5-{5-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-1,3,4-thiadiazol-2-yl}-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.46 g, 63% yield). LCMS: ESI(+) [M+H] + =472.40. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.3Hz,1H),8.65(br.q,J=4.9Hz,1H),8.63(s,1H),8.16(s,1H),7.87(d,J=4.8 Hz,1H),7.11(d,J=4.8Hz,1H),4.46(t,J=5.4Hz,1H),3.11(d,J=5.4Hz,2H),3.07(d,J=4.8Hz,3H),2.01-1.90(m,6H),1.57-1.46(m,6H).

[0221] Step 3: To a solution of 7-(5-{5-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-1,3,4-thiadiazol-2-yl}-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.46 g, 3.10 mmol, 1 equiv.) in DCM (900 mL, 3.44 mM) was added Dess-Martin periodinane (1.71 g, 4.02 mmol, 1.3 equiv.). The reaction mixture was stirred at room temperature for 2 hours and then quenched with 20% aqueous NaSO and saturated aqueous NaHCO. The mixture was stirred until the aqueous layer became clear. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated NaHCO, water, and brine. The combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting crude was triturated with Et2O, filtered, and the filtered solid was washed with a mixture of DCM / Et2O (1:1), Et2O and pentane to give the title compound (1.28 g, 88% yield). LCMS: ESI(+) [M+H] + =470.15. 1 H NMR(300MHz,DMSO-d6)δ:9.49(s,1H),8.85(d,J=2.2Hz,1H),8.75(d,J=2.2Hz,1H),8.67(s,1H),8.64(q,J=5.1Hz,1H), 8.19(s,1H),7.88(d,J=4.8Hz,1H),7.13(d,J=4.8Hz,1H),3.09(d,J=4.9Hz,3H),2.09-1.98(m,6H),1.82-1.71(m,6H).

[0222] Intermediate V: 7-[4-(methylamino)-5-{5-[4-(piperidin-4-yl)piperazin-1-yl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0223] [ka]

[0224] This compound was synthesized according to the same procedure as described for intermediate T, except that tert-butyl 4-piperazin-1-ylpiperidine-1-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. LCMS C 25 H 28 N 10 S theoretical value: 500.2, measured value: m / z = 501.5 [M+H] + .

[0225] Intermediate W: 7-{4-[(3-methyloxetan-3-yl)amino]-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0226] [ka]

[0227] Step 1: DIPEA (17.96 mL, 138.98 mmol, 3.5 equiv.) was added to a stirred solution of 3-methyl-3-oxetanamine-HCl (4.9 g, 39.7 mmol, 1 equiv.) in DMF (39.7 mL, 1 M). 2-Chloro-4-fluoropyridine (7.4 mL, 79.4 mmol, 2 equiv.) was then added, and the mixture was heated to 100° C. in a sealed tube for 32 h. Excess reagent and DMF were removed by rotary evaporation. The residue (16.25 g) was diluted with DCM and adjusted to pH = 8 with saturated aqueous NaHCO3. The layers were separated, and the organic layer was extracted four times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated on a rotary evaporator. The crude was purified by FC (hexane / ethyl acetate) to give 5.17 g (54% yield) of 2-chloro-N-(3-methyloxetan-3-yl)pyridin-4-amine. [M+H] + =199.50 m / z. 1H NMR (300MHz, DMSO-d6) δ7.86(d,J=5.8Hz,1H),7.41(s,1H),6.36-6.25(m,2H),4.60(d,J=6.1Hz,2H),4.51(d,J=6.2Hz,2H),1.56(s,3H).

[0228] Step 2: To a solution of 2-chloro-N-(3-methyloxetan-3-yl)pyridin-4-amine (5.904 g, 24.668 mmol, 1.0 equiv.) in dimethoxyethane (123.33 mL, 0.2 M) in a 400 mL glass reactor, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (9.293 g, 34.532 mmol, 1.4 equiv.) and tribasic potassium phosphate (10.686 g, 49.335 mmol, 2.0 equiv.) were added. The mixture was degassed by evacuating and backfilling the reactor with argon (three times). Xphos Pd G3 (1.491 g, 1.726 mmol, 0.07 equiv) was added, and the evacuation-backfilling procedure was repeated three times. The reactor was sealed, and the mixture was stirred at 120 °C overnight. The mixture was diluted with DCM and concentrated. The residue was purified by silica gel FC (DCM / EA 100:0 to 0:100) to give 4.83 g (55% yield) of 7-{4-[(3-methyloxo- {(1,2-b)-pyridin-3-yl)amino}pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile was obtained as a yellow solid. [M+H] + =306.46 m / z. 1 H NMR(300MHz,DMSO-d6)δ8.80(d,J=2.2Hz,1H),8.68(d,J=2.2Hz,1H),8.19(d,J=5.7Hz,1H),7.81-7.71(m,2H),7.28( s,1H),7.09(d,J=4.8Hz,1H),6.29(dd,J=5.7,2.3Hz,1H),4.69(d,J=6.0Hz,2H),4.55(d,J=6.0Hz,2H),1.64(s,3H).

[0229] Step 3: To a solution of 7-{4-[(3-methyloxetan-3-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.944 g, 11.625 mmol, 1.0 equiv) in anhydrous acetonitrile (136.78 mL, 0.085 M) and anhydrous dimethylformamide (35.23 mL, 0.33 M) was added a solution of N-bromosuccinimide (1.966 g, 11.046 mmol, 0.95 equiv) in anhydrous acetonitrile (14.53 mL, 0.8 M) in one portion at 0° C. The mixture was stirred at 0° C. for 45 minutes. The precipitate formed was filtered off and dried to give 7-{5-bromo-4-[(3-methyloxetan-3-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.1 g, 5.465 mmol, 47%). The filtrate was concentrated and purified by FC (silica gel, DCM to DCM / EA 7:3) to give a further 1.57 g (35% yield) of 7-{5-bromo-4-[(3-methyloxetan-3-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile. [M+H] + =386.26 m / z. 1 H NMR(300MHz,DMSO-d6)δ8.82(d,J=2.2Hz,1H),8.80(d,J=2.2Hz,1H),8.43(s,1H),7.79(d,J=4.8Hz,1H),7 .64(s,1H),7.09(d,J=4.8Hz,1H),6.78(s,1H),4.79(d,J=6.3Hz,2H),4.58(d,J=6.4Hz,2H),1.71(s,3H).

[0230] Step 4: To a solution of 7-{5-bromo-4-[(3-methyloxetan-3-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.65 g, 9.499 mmol, 1.0 equiv) in anhydrous dioxane (279.39 mL, 0.034 M) in a glass pressure reactor was added tert-butyl 4-(1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (2.594 g, 9.499 mmol, 1.0 equiv). The reactor was evacuated and backfilled with argon three times. Palladium(II) acetate (0.213 g, 0.949 mmol, 0.1 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.099 g, 1.899 mmol, 0.2 equiv.), cesium carbonate (12.38 g, 37.997 mmol, 4.0 equiv.), and copper(I) iodide (0.362 g, 1.901 mmol, 0.2 equiv.) were added and the reaction vessel was sealed. The mixture was stirred at 105 °C for 3 h. UPLC showed partial conversion of SM. Palladium(II) acetate (0.107 g, 0.477 mmol, 0.05 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.55 g, 0.951 mmol, 0.1 equiv.), cesium carbonate (6.19 g, 18.998 mmol, 2.0 equiv.), and copper(I) iodide (0.181 g, 0.95 mmol, 0.1 equiv.) were added, and the reactor was evacuated and backfilled with argon three times. The reactor was resealed, and the mixture was stirred at 105 °C overnight. Additional portions of palladium(II) acetate (0.107 g, 0.477 mmol, 0.05 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.55 g, 0.951 mmol, 0.1 equiv.), cesium carbonate (6.19 g, 18.998 mmol, 2.0 equiv.), and copper(I) iodide (0.181 g, 0.95 mmol, 0.1 equiv.) were added, and after evacuating and backfilling with argon and sealing, the mixture was stirred at 105 °C for 4 h. The mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by FC (silica gel, DCM to DCM / ethyl acetate 1:1) to give 1.11 g (20% yield) of the title compound was obtained. Two further impure fractions (F2-0.97 g and F4-0.73 g) were repurified by FC (silica, DCM to DCM / ethyl acetate 1:1), combined, and repurified again (silica, DCM to DCM / ACN 6:4) to give a further 0.31 g (6% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(3-methyloxetan-3-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate. [M+H] + =573.92 m / z. 1 H NMR(300MHz,DMSO-d6)δ8.92(s,1H),8.84(t,J=1.8Hz,2H),8.55(s,1H),7.89-7.84(m,2H),7.12(d,J=4 .8Hz,1H),4.78(d,J=6.4Hz,2H),4.71(d,J=6.2Hz,2H),3.54(q,J=5.5Hz,8H),1.79(s,3H),1.44(s,9H).

[0231] Step 5: To a solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(3-methyloxetan-3-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (1.134 g, 1.917 mmol, 1.0 equiv) in anhydrous dichloromethane (35.2 mL, 32.0 vol), trifluoroacetic acid (1.477 mL, 19.171 mmol, 9.998 equiv) was added. The mixture was stirred at room temperature for 90 minutes. UPLC showed no conversion. Trifluoroacetic acid (0.739 mL, 9.592 mmol, 5.003 equiv) was added and stirring was continued for 90 minutes. UPLC showed complete conversion. The mixture was concentrated and co-evaporated with DCM three times. The residue was triturated with diethyl ether (150 mL). The resulting solid (TFA salt) was purified by RP FC (C18 silica, water to water / ACN Purification by 1:1 elution with 0.1% FA gave 0.545 g (59% yield) of 7-{4-[(3-methyloxetan-3-yl)amino]-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile as the TFA salt. LCMS: ESI(+) [M+H] + =474.32. 1 H NMR(300MHz,DMSO-d6)δ8.92(s,3H),8.86(q,J=2.2Hz,2H),8.58(s,1H),7.87(d,J=4.9Hz,2H),7.13(d, J=4.8Hz,1H),4.78(d,J=6.3Hz,2H),4.73(d,J=6.2Hz,2H),3.83-3.72(m,4H),3.32(s,4H),1.79(s,3H).

[0232] Intermediate X: 7-{4-[(cyanomethyl)amino]-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile; trifluoroacetate.

[0233] [ka]

[0234] Step 1: DIPEA (23.4 mL, 133.6 mmol, 3 equiv) was added to a stirred solution of 2-bromo-4-fluoropyridine (7.84 g, 44.55 mmol, 1 equiv) in NMP (63 mL, 0.71 M). Aminoacetonitrile-HCl (6.31 g, 66.82 mmol, 1.5 equiv) was added portionwise, and the mixture was heated to 120 °C in a pressure vial. After 12 h, additional aminoacetonitrile-HCl (3 g, 31.77 mmol, 0.7 equiv) and DIPEA (16 mL, 91.35 mmol, 2 equiv) were added. The reaction was stirred at 120 °C for 12 h. The reaction was diluted with water and extracted with EA. The EA was washed with water, brine, and dried over Na2SO4. The crude material was purified with FC hexane / EA (0-95%) to give 6.0 g (64% yield) of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile. [M+H] + =214.1 m / z. 1 H NMR(300MHz,DMSO-d6)7.94(1H,d,J=5.7Hz),7.43(1H,t,J=6.4Hz),6.88(1H,d,J=2.2Hz),6.70(1H,dd,J=5.7,2.2Hz),4.41(2H,d,J=6.4Hz).

[0235] Step 2: To a solution of 2-[(2-bromopyridin-4-yl)amino]acetonitrile (6.5 g, 30.65 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (11.55 g, 42.91 mmol, 1.4 equiv.), and Xphos Pd G3 (1.3 g, 1.53 mmol, 0.05 equiv.) in DME (153 mL, 0.2 M) was added 2 M KPO4 solution (31 mL, 61.31 mmol, 2.0 equiv.). The solution was degassed with argon for 2-3 min and then heated at 120 °C for 5 h. UPLC showed complete conversion of the starting material. The resulting solution was diluted with DCM and concentrated to dryness. The crude material was purified by FC eluting with EA:DCM (0-85%) to give 4.29 g (47% yield) of 7-{4-[(cyanomethyl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile. [M+H] + =275.38 m / z. 1 H NMR(300MHz,DMSO-d6)8.82(1H,d,J=2.2Hz),8.65(1H,d,J=2.3Hz),8.36(1H,d,J=5.6Hz),8.03(1H,d,J=2.3Hz),7. 79(1H,d,J=4.7Hz),7.40(1H,t,J=6.4Hz),7.10(1H,d,J=4.8Hz),6.69(1H,dd,J=5.7,2.4Hz),4.42(2H,d,J=6.3Hz).

[0236] Step 3: 7-{4-[(cyanomethyl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (4.81 g, 17.54 mmol, 1 equiv.) was dissolved in a 10:5:1 ACN / DCM / DMF mixture (1.5 L, 0.011 M), and N-bromosuccinimide (2.81 g, 15.78 mmol, 0.9 equiv.) was added in one portion at room temperature. The reaction was stirred at room temperature for 30 minutes. After completion, the mixture was evaporated, and the crude material was purified by FC eluting with DCM / EtOAc to give 2.0 g (35% yield) of 7-{5-bromo-4-[(cyanomethyl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile. [M+H]+ =355.18 m / z. 1 H NMR(300MHz,DMSO-d6)8.84(1H,d,J=2.3Hz),8.64(1H,d,J=2.2Hz),8.52(1H,s),8.14(1H,s ),7.79(1H,d,J=4.8Hz),7.12(1H,d,J=4.8Hz),7.00(1H,t,J=6.2Hz),4.47(2H,d,J=6.2Hz).

[0237] Step 4: 7-{5-bromo-4-[(cyanomethyl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.04 g, 2.83 mmol, 1.0 equiv) was dissolved in dioxane (30 mL, 0.1 M) and DMF (10 mL, 0.3 M) in a pressure-resistant vial, followed by bis(pinacolato)diboron (1.44 g, 5.66 (0.86 g, 8.789 mmol, 3.1 equiv.) and KOAc (0.86 g, 8.789 mmol, 3.1 equiv.) were added. The solution was degassed with argon for several minutes, and Pd(PPh3)2Cl2 (0.2 g, 0.283 mmol, 0.1 equiv.) was added, followed by repeated degassing. The reaction mixture was stirred at 80 °C for 24 h. UPLC showed complete conversion. The reaction mixture was diluted with EtOAc, washed with HO and brine, and dried over Na2SO4. The crude material was triturated with hexane to remove excess bis(pinacolato)diboron, filtered, dried, and used in the next step without further purification.

[0238] Step 5: To a solution of 7-{4-[(cyanomethyl)amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.17 g, 7.93 mmol, 1.0 equiv.) in anhydrous dioxane (140 mL, 0.06 M) in a glass reactor was added tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (2.77 g, 7.93 mmol, 1.0 equiv.). The reactor was evacuated and filled with argon three times. Tri-tert-butylphosphonium tetrafluoroborate (0.23 g, 0.793 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.363 g, 0.397 mmol, 0.05 equiv.), and cesium fluoride (3.61 g, 23.79 mmol, 3.0 equiv.) were added. The evacuation-backfilling process was repeated three times, the reactor was sealed, and the mixture was stirred at 70 °C for 12 h. Additional amounts of tri-tert-butylphosphonium tetrafluoroborate (0.23 g, 0.793 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.363 g, 0.397 mmol, 0.05 equiv.), and cesium fluoride (3.61 g, 23.79 mmol, 3.0 equiv.) were added. The evacuation-backfilling process was repeated three times, the reactor was sealed, and the mixture was stirred at 70° C. for 12 h. The mixture was cooled to room temperature, diluted with DCM (200 mL), and filtered. The residue was purified twice by FC (DCM / i-PrOH and DCM / acetone) to give 0.108 g (3% yield) of tert-butyl 4-(5-{4-[(cyanomethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate. [M+H] + =543.65 m / z. 1H NMR(300MHz,DMSO-d6)δ8.91-8.83(2H,m),8.68(1H,d,J=2.3Hz),8.61(1H,s),8.30(1H,s),7.8 8(1H,d,J=4.8Hz),7.15(1H,d,J=4.9Hz),4.70(2H,d,J=6.1Hz),3.64-3.48(9H,m),1.44(9H,s).

[0239] Step 6: To a solution of tert-butyl 4-(5-{4-[(cyanomethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (108 mg, 0.199 mmol, 1.0 equiv.) in anhydrous dichloromethane (5 mL, 0.4 M) was added trifluoroacetic acid (5 mL, 65.68 mmol, 330 equiv.). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated and co-evaporated with DCM three times. The residue was triturated with diethyl ether, filtered, and washed with diethyl ether. The resulting solid was purified by RP chromatography. Purification by FC (C18 silica, ACN / HO with 0.1% FA) gave 66.5 mg (58% yield) of 7-{4-[(cyanomethyl)amino]-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile; trifluoroacetate (N-51) as a yellow solid. LCMS: ESI(+) [M+H] + =443.21. 1 H NMR(300MHz,DMSO-d6)δ9.08(2H,br.s),8.87(1H,d,J=2.3Hz),8.83(1H,t,J=6.2Hz,overlapped ),8.68(1H,d,J=2.2Hz),8.62(1H,s),8.30(1H,s),7.88(1H,d,J=4.8Hz),7.15(1H,d,J=4.8Hz) ,4.71(2H,d,J=6.1Hz),3.86-3.68(4H,m),3.35-3.27(4H,m).

[0240] Intermediate Y: 7-{4-[(oxetan-3-yl)amino]-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0241] [ka]

[0242] Step 1: DIPEA (27 mL, 156 mmol, 3.5 equiv.) was added to a cooled, stirred solution of oxetan-3-amine-HCl (4.89 mg, 44.6 mmol, 1 equiv.) in DMF (45 mL, 1 M). 2-Chloro-4-fluoropyridine (8.3 mL, 90 mmol, 2 equiv.) was then added, and the mixture was heated to 90 °C in a sealed tube. Upon completion, the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic extract was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by FC (acetone / DCM 10-50%) to give 2-chloro N-(oxetan-3-yl)pyridin-4-amine (3.2 g, 38% yield). LCMS: ESI (+) [M+H] + =185.10. 1 H NMR(300MHz,DMSO-d6)7.85(d,J=5.8Hz,1H),7.63(d,J=6.3Hz,1H),6.55-6.33(m ,2H),4.85(t,J=6.6Hz,2H),4.65(dt,J=12.8,6.3Hz,1H),4.41(t,J=6.1Hz,2H).

[0243] Step 2: To a solution of 2-chloro-N-(oxetan-3-yl)pyridin-4-amine (2.59 g, 13.9 mmol, 1.0 equiv.) in DME (200 mL, 0.07 M) was added KPO (6.09 g, 27.8 mmol, 2 equiv.). The solution was degassed with argon for 20 minutes, and then 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.24 g, 19.5 mmol, 1.4 equiv.) and XPhos Pd G3 (841 mg, 0.97 mmol, 0.07 equiv.) were added. The pressure vessel was sealed and heated to 120 °C overnight. The reaction was filtered through a pad of Celite, which was washed with DCM and MeOH. The mother liquor was evaporated under reduced pressure and the residue was purified by FC (5-50% ACN in DCM) to give 7-{4-[(oxetan-3-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.9 g, 46% yield). LCMS: ESI(+) [M+H] + =292.37. 1 H NMR (300 MHz, DMSO-d6) δ 8.8 0(d,J=2.2Hz,1H),8.67(d,J=2.2Hz,1H),8.21(d,J=5.7Hz,1H),7.85(d,J=2.1Hz,1H),7.76(d,J=4.8Hz,1H),7.52(d,J=5.9Hz,1 H),7.08(d,J=4.8Hz,1H),6.40(dd,J=5.7,2.3Hz,1H),4.89(t,J=6.5Hz,2H),4.68(dt,J=12.6,6.1Hz,1H),4.50(t,J=6.1Hz,2H).

[0244] Step 3: A solution of 7-{4-[(oxetan-3-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.9 g, 6.52 mmol, 1 equiv.) in a 4:1 mixture of ACN / DMF (75 mL, 0.086 M) was cooled to 0 °C. N-Bromosuccinimide (1.1 g, 6.2 mmol, 0.95 equiv.) was dissolved in ACN (5 mL) and added in one portion. The solution was stirred at 0 °C until complete (4 min) and monitored by TLC (AcOEt / Hex 1:1). A precipitate formed. The precipitate was collected by filtration, and the solid was dried extensively to remove residual DMF and ACN, affording 2-bromo-1,3,4-thiadiazole (1.35 g, 56% yield). LCMS: ESI (+) [M+H] + =370.20. 1 H NMR(300MHz,DMSO-d6)δ8.82(d,J=2.2Hz,1H),8.79(d,J=2.2Hz,1H),8.45(s,1H),7.78(d,J=4.8Hz,1H ),7.75(s,1H),7.09(d,J=4.8Hz,1H),6.87(d,J=3.1Hz,1H),4.94(d,J=3.2Hz,2H),4.76-4.66(m,3H).

[0245] Step 4: To a solution of 2-bromo-1,3,4-thiadiazole (5 g, 30.3 mmol, 1.0 equiv.) and tert-butyl piperazine-1-carboxylate (14.4 g, 75.75 mmol, 2.5 equiv.) in n-butanol (63 mL, 0.48 M) was added DIPEA (22 mL, 121.2 mmol, 4.0 equiv.). The reaction mixture was heated in an oil bath at 120 °C for 1 h. The reaction mixture was cooled and concentrated in vacuo to give the crude product. It was diluted with 50 mL of AcOEt and 100 mL of HO and extracted with AcOEt (5 × 50 mL). The combined organic layers were dried over NaSO and evaporated in vacuo to give the crude product as a deep red crystalline solid. The compound was purified by FC (Hex / AcOEt 0-100%) to give 7-{5-bromo-4-[(oxetan-3-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.73 g, 69% yield). LCMS: ESI(+) [M+H]+ =271.20, 1 H NMR (300MHz, DMSO-d6) δ: 8.85 (s, 1H), 3.47 (s, 8H), 1.43 (s, 9H).

[0246] Step 5: 7-{5-bromo-4-[(oxetan-3-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.3 g, 3.51 mmol, 1 equiv.), tert-butyl 4-(1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate ( A suspension of CsCO (1.05 mg, 3.86 mmol, 1.1 equiv.), CuI (134 mg, 0.7 mmol, 0.2 equiv.), Xantphos (406 mg, 0.7 mmol, 0.2 equiv.), and CsCO (4.58 mg, 14 mmol, 4.0 equiv.) was degassed with argon for 15 min, and Pd(OAc) (80 mg, 0.35 mmol, 0.1 equiv.) was added. The pressure vessel was sealed and heated at 105 °C overnight. The reaction mixture was filtered through Celite, which was washed with AcOEt, and the solvent was evaporated in vacuo. The crude product was purified by FC (320 g column with 20 g silica dry loading, 25 CV ACN / DCM gradient 0-100%). The residue was triturated with EtO (sonication for 15 min) and filtered to give 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxetan-3-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (692 mg, 35% yield). LCMS: ESI(+)[M+H] + =560.58. 1H NMR(300MHz,DMSO-d6)δ8.94(d,J=4.8Hz,1H),8.85(d,J=2.3Hz,1H),8.82( d,J=2.2Hz,1H),8.56(s,1H),7.91(s,1H),7.86(d,J=4.9Hz,1H),7.12(d,J =4.9Hz,1H),5.07(t,J=6.6Hz,2H),4.88(dd,J=11.4,5.9Hz,1H),4.59(t,J =6.2Hz,2H),3.55(d,J=5.6Hz,7H),3.47(s,5H),1.44(s,7H),1.43(s,6H).

[0247] Step 6: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxetan-3-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (692 mg, 1.24 mmol, 1.0 equiv) in HFIP (4.0 mL) was heated in a microwave reactor at 140° C. for 1 h. The reaction mixture was purified by preparative HPLC to give the title compound (64 mg, 18% yield). LCMS: ESI(+) [M+H] + =459.96. 1 H NMR(300MHz,DMSO-d6)δ8.94(d,J=4.6Hz,1H),8.84(d,J=2.3Hz,1H),8.81(d,J=2.2Hz,1H),8.55(s,1H),7.90(s,1H),7.85(d,J=4.8 Hz,1H),7.12(d,J=4.9Hz,1H),5.06(t,J=6.7Hz,2H),4.93-4.82(m,1H),4.59(t,J=6.2Hz,2H),3.56-3.48(m,4H),2.98-2.83(m,4H).

[0248] Intermediate Z: 7-[4-(cyclopropylamino)-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0249] [ka]

[0250] Step 1: To a stirred solution of tert-butyl piperazine-1-carboxylate (8 g, 42.9 mmol, 1.0 equiv.) in anhydrous THF (150 mL, 0.3 M), TEA (19 mL, 129 mmol, 3.0 equiv.) and 1,1'-thiocarbonyldiimidazole (11.5 g, 51.54 mmol, 1.2 equiv.) were added, and the reaction mixture was stirred at room temperature for 2 hours. The solution was then transferred dropwise to a solution of hydrazine monohydrate (9.6 mL, 129 mmol, 3 equiv.) in THF (50 mL). The reaction was monitored for completion by TLC. The mixture was diluted with water (500 mL), and the aqueous layer was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over NaSO, and concentrated under reduced pressure. The residue was recrystallized from AcOEt / Hex (1:2) to give tert-butyl 4-(aminocarbamothioyl)piperazine-1-carboxylate (10.09 g, 89% yield). ESI(-)[MH] + =259.38. 1 H NMR (300MHz, DMSO-d6)d9.13(s,1H),4.76(s,2H),3.79-3.62(m,4H),3.42-3.25(m,4H),1.41(s,9H).

[0251] Step 2: To a solution of starting 4,6-dichloronicotinic acid (5.645 g, 29.11 mmol, 1.1 equiv) in dry DCM (90 mL, 0.3 M) under argon was added EtN (4.4 mL, 1.2 equiv) and the solution was cooled to −15° C. Isobutyl chloroformate (3.85 mL, 1.1 equiv) was added dropwise while maintaining the temperature at −15° C. The solution was then held at −15° C. for 1 h. tert-Butyl 4-(aminocarbamothioyl)piperazine-1-carboxylate (6.89 g, 26.2 mmol, 1.0 equiv) was then added in portions and the reaction was stirred at room temperature overnight. Upon completion, the solution was treated with NaHCO and extracted with DCM (3×50 mL). The combined organic layers were dried over NaSO, filtered, and evaporated to dryness. The crude residue was triturated with EtO and filtered to give tert-butyl 4-{[(4,6-dichloropyridin-3-yl)formohydrazide]methanethioyl}piperazine-1-carboxylate (8.2 g, 70% yield). ESI(-)[MH] + =434.00. 1 H NMR (300MHz, DMSO-d6) δ10.68(s,1H),9.94(s,1H),8.71(s,1H),7.97(s,1H),3.99-3.80(m,4H),3.47-3.37(m,4H),1.42(s,9H).

[0252] Step 3a: A solution of tert-butyl 4-{[(4,6-dichloropyridin-3-yl)formohydrazide]methanethioyl}piperazine-1-carboxylate (4.211 g, 9.21 mmol, 1.0 equiv) in sulfuric acid (31 mL, 552.6 mmol, 60 equiv) was stirred overnight at room temperature. With vigorous stirring, the reaction was poured onto ice (approximately 200 mL). KCO was then carefully added portionwise until the pH was >9. The KSO was filtered off and washed several times with DCM. The product was extracted from the aqueous phase with DCM (3 × 200 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure to give 1-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine (2.276 g, 77% yield). ESI(+)[M+H] +=316.28. 1 H NMR (300MHz, DMSO-d6) δ8.94 (s, 1H), 8.02 (s, 1H), 3.50-3.45 (m, 4H), 2.87-2.78 (m, 4H).

[0253] Step 3b: To a solution of 1-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine (2.276 g, 7.2 mmol, 1.0 equiv.) in DCM (14 mL, 0.5 M), TEA (1.2 mL, 8.6 mmol, 1.2 equiv.) was added, the reaction was stirred for 5 minutes, and BocO (1.9 g, 8.6 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at room temperature for 1 hour. Upon completion, the solution was evaporated to dryness under reduced pressure. The crude solid was suspended in hexane and filtered to give tert-butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (2.8 g, 93% yield). ESI(+) [M+H] + =360.34. 1 H NMR (300MHz, DMSO-d6) δ 8.94 (s, 1H), 8.04 (s, 1H), 3.63-3.46 (m, 8H), 1.43 (s, 9H).

[0254] Step 4: tert-Butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (1.4 g, 3.4 mmol) in a 1:3 mixture of t-butanol / THF (45 mL, 0.075 M) To a solution of 4-{5-[6-chloro-4-(cyclopropylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (1.33 g, 81%) was added cyclopropylamine (2.4 mL, 33.6 mmol, 10 equiv.) and the reaction mixture was heated to 90° C. for 24 h. Upon completion, the solution was evaporated under reduced pressure, diluted with water (100 mL), and extracted with DCM (20 mL×3). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl 4-{5-[6-chloro-4-(cyclopropylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (1.33 g, 81%). ESI(+)[M+H] + =437.70.1 H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.23(s,1H),7.05(s,1H),3.52(s,8H), 2.73-2.59(m,1H),1.43(s,9H),0.90(q,J=6.6Hz,2H),0.57(p,J=4.8Hz,2H).

[0255] Step 5: To a solution of tert-butyl 4-{5-[6-chloro-4-(cyclopropylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (1.33 g, 3 mmol, 1.0 equiv.) in DME (40 mL, 0.07 M) was added KPO (1.332 g, 6 mmol, 2.0 equiv.), and the mixture was degassed with argon for 10 min. 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.147 g, 4.262 mmol, 1.4 equiv.) and XPhos Pd G (0.184 g, 0.213 mmol, 0.07 equiv.) were added, and the pressure vessel was sealed. The mixture was stirred at 120°C overnight. The solvent was evaporated under reduced pressure. The crude material was purified by FC (0-10% i-PrOH / DCM over 25 CV) to give tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (120 mg, 20% yield). ESI(+) [M+H] + =544.48. 1 H NMR(300MHz,DMSO-d6)δ9.36(s,2H),9.12(s,1H),8.92(s,1H),8.84(s,1H),8.60(s,1H),8.52(s,1H),8 .05(s,1H),7.19(s,1H),3.80(s,4H),3.30(s,4H),2.83(s,1H),1.41(s,9H),1.06(s,2H),0.70(s,2H).

[0256] Step 6: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (120 mg, 0.22 mmol, 1.0 equiv) in DCM (1 mL, 0.3 M) was cooled to 0 °C. TFA (0.17 mL, 2.2 mmol, 10 equiv) was then added dropwise and the mixture was stirred at room temperature for 3 h. Upon completion, the mixture was evaporated to dryness. The crude was suspended in EtO and sonicated for 30 min. The suspension was filtered to afford 95 mg (45% yield) of the title compound (TFA salt) as a yellow solid. LCMS: ESI(+) [M+H] + =444.48. 1 H NMR(300MHz,DMSO-d6)δ9.36(s,2H),9.12(s,1H),8.92(s,1H),8.84(s,1H),8.60(s,1H),8.52(s ,1H),8.05(s,1H),7.19(s,1H),3.80(s,4H),3.30(s,4H),2.83(s,1H),1.06(s,2H),0.70(s,2H).

[0257] Intermediate AA: 7-[4-(ethylamino)-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0258] [ka]

[0259] Step 1: A mixture of tert-butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (1.4 g, 3.36 mmol, 1.0 equiv.) and a 2 M solution of ethylamine in THF (2 mL, 7.1 mmol, 20.0 equiv.) in tert-butanol (22 mL, 0.15 M) was heated at 90 °C overnight. All volatiles were then evaporated under reduced pressure, and the residue was dissolved in dichloromethane, washed with water, dried, and the solvent evaporated. The crude material was triturated with hexane to give 1.35 g (94% yield) of tert-butyl 4-{5-[6-chloro-4-(ethylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate. ESI (+) [M+H] + =425.64. 1 H NMR (300MHz, DMSO-d6), d:8.59(t,J=5.0Hz,1H),8.20(s,1H),6.81(s,1H),3.52(m,8H),3.32(brq,2H),1.43(s,9H),1.23(t,J=7.2Hz,3H).

[0260] Step 2: tert-Butyl 4-{5-[6-chloro-4-(ethylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (1.6 g, 3.77 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.42 g, 5.27 mmol, 1.4 equiv.), KPO (1.648 g, 7.531 mmol, 2.0 equiv.), and XPhos Pd G (0.228 g, 0.264 mmol, 0.07 equiv.) were suspended in dimethoxymethane (54 mL, 0.07 M). The mixture was degassed with argon for 20 min and stirred at 120 °C overnight. The crude was purified by FC (silica gel, dichloromethane / acetonitrile 1:1) to give 1.2 g (60% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow solid. ESI(+) [M+H] + =533.0. 1 H NMR(300MHz,DMSO-d6),δ:8.84(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.48(m,1H),8.16(s,1H), 7.85(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),3.54(brm,10H),1.44(s,9H),1.34(t,J=7.1Hz,3H).

[0261] Step 3: tert-Butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (1.2 g, 2.25 mmol, 1.0 equiv.) was dissolved in acetic acid (15 mL, 0.15 M), HCl in diethyl ether (6 g, 22.57 mmol, 10 equiv.) was added, and the reaction was stirred at room temperature for 2 h. UPLC monitoring was applied. All volatiles were then evaporated, and the crude residue was triturated with a mixture of 2-propanol and diethyl ether to give 0.5 g (50% yield) of the title compound as a yellow solid. LCMS: ESI(+) [M+H] + =432.21. 1 H NMR(300MHz,DMSO-d6),δ:8.83(s,1H),8. 71(s,1H),8.49(d,J=13.2Hz,2H),8.15(s,1H),7.84(d,J=4.7Hz,1H),7.11(d,J=4.6H z,1H),4.12(brm,1H),3.50(m,4H),3.44(brq,2H),2.90(m,4H),1.34(t,J=7.1Hz,3H).

[0262] Intermediate AB: 7-[4-(ethylamino)-5-[5-(piperazin-1-yl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile tetrahydrochloride.

[0263] [ka]

[0264] Step 1: A solution of tert-butyl 4-{[(4,6-dichloropyridin-3-yl)formohydrazide]methanethioyl}piperazine-1-carboxylate (0.11 g, 0.25 mmol, 1.0 equiv.) and p-toluenesulfonyl chloride (0.082 g, 0.43 mmol, 1.7 equiv.) in dry pyridine (1.3 mL, 0.2 M) was heated with stirring at 75 °C for 1.5 h. All volatiles were then evaporated at low pressure, and the crude material was purified by flash chromatography (silica gel, DCM / 2-PrOH, 9:1) to afford 0.06 g (52% yield) of tert-butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate as an off-white crystalline product. ESI (+) [M+H] + =418.8. 1 H NMR (300MHz, DMSO-d6), d: 8.93 (s, 1H), 8.05 (s, 1H), 3.51 (s, 8H), 1.43 (s, 9H).

[0265] Step 2: tert-Butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate (0.36 g, 0.865 mmol, 1.0 equiv.) was dissolved in tert-butanol (6 mL, 0.15 M) and 10% ethylamine in THF (2.0 mL, 4.32 mmol, 5 equiv.) was added. The resulting mixture was heated at 80 °C overnight, cooled to room temperature, dissolved in dichloromethane, washed with water, and the organic phase was dried over Na SO , filtered, and evaporated to dryness under reduced pressure to give 0.32 g (77% yield) of tert-butyl 4-{5-[6-chloro-4-(ethylamino)pyridin-3-yl]-1,3,4-oxadiazol-2-yl}piperazine-1-carboxylate as an off-white solid. ESI (+) [M+H] + =409.63. 1 H NMR (300MHz, DMSO-d6), δ:8.46(s,1H),7.83(d,J=5.2Hz,1H),6.85(s,1H),3.51(s,8H),3.39(s,2H),1.43(s,9H),1.23(t,J=7.1Hz,3H).

[0266] Step 3: tert-Butyl 4-{5-[6-chloro-4-(ethylamino)pyridin-3-yl]-1,3,4-oxadiazol-2-yl}piperazine-1-carboxylate (0.3 g, 0.74 mmol, 1 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxylate ( ... Nitrile (0.28 g, 1.03 mmol, 1.4 equiv.), KPO (0.35 g, 1.47 mmol, 2 equiv.), and XPhos Pd G3 (0.05 g, 0.052 mmol, 0.07 equiv.) were suspended in dimethoxyethane (11 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred at 120 °C overnight. The crude product was purified by flash chromatography (silica gel, dichloromethane / 2-propanol) to afford 0.2 g (51% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow solid. ESI (+) [M+H] + =516.71. 1 H NMR(300MHz,DMSO-d6),δ:8.85(d,J=2.2Hz,1H),8.77(s,1H),8.74(d,J=2.2Hz,1H),8.19(s,1H),7.87(d,J=4. 8Hz,1H), 7.74(t,J=5.3Hz,1H),7.12(d,J=4.8Hz,1H),3.58-3.41(m,10H),1.44(s,9H),1.34(t,J=7.1Hz,3H).

[0267] Step 4: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (0.2 g, 0.38 mmol, 1 equiv.) was dissolved in glacial acetic acid (2.51 mL, 0.15 M) and 1 M HCl in diethyl ether (0.915 g, 3.76 mmol, 10 equiv.) was added. The resulting mixture was stirred for 2 h. Then, all volatiles were evaporated under reduced pressure. The residue was triturated with dry diethyl ether to afford 0.18 g (81% yield) of the title compound as a yellow crystalline solid. LCMS: ESI(+) [M+H] + =416.25.

[0268] 1 H NMR(300MHz,DMSO-d6),δ:9.53(s,2H),9.00(d,J=2.1Hz,1H),8.86(d,J=2.2Hz,1H),8.75(s,2H),8.28(d,J=5.0Hz, 1H),8.12(s,1H),7.24(d,J=5.0Hz,1H),3.86(s,4H),3.65(d,J=12.8Hz,2H),3.29(brm,4H),1.35(t,J=7.1Hz,3H).

[0269] Intermediate AC: 7-(4-{[(1R)-1-cyanoethyl]amino}-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0270] [ka]

[0271] Step 1: To a solution of tert-butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (10.0 g, 24.02 mmol, 1.0 equiv.) in anhydrous dimethyl sulfoxide (80 mL, 0.3 M), potassium fluoride (1.61 g, 27.623 mmol, 1.15 equiv.) and 18-crown-6 (3.18 g, 12.01 mmol, 0.5 equiv.) were added. The reaction mixture was stirred at 105 °C for 24 hours. After completion of the reaction, it was diluted with water (100 mL), and the aqueous layer was extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was triturated with hexanes and then purified by silica gel flash chromatography eluting with 0-50% EtOAc in hexanes to give 6.7 g (70% yield) of tert-butyl 4-[5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as an off-white solid. LCMS: [C 16 H 19 ClFN5O2S], desired mass 399.1, measured mass = 399.9[M+H + ]. 1 H NMR (300MHz, CDCl3) δ9.21(d,J=9.8Hz,1H),7.22(d,J=9.8Hz,1H),3.62(s,8H),1.49(s,9H).

[0272] Step 2: tert-Butyl 4-[5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (6.7 g, 16.76 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.41 g, 20.10 mmol, 1.2 equiv.), potassium phosphate tribasic (7.11 g, 33.51 mmol, 2.0 equiv.), and XPhos Pd G3 (0.99 g, 1.17 mmol, 0.07 equiv.) were suspended in dimethoxyethane (240 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and warmed to 120 °C overnight. After the reaction was complete, it was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM (5 CV), 0-30% ACN in DCM (15 CV), and 30% ACN in DCM, followed by trituration with EtO to obtain 950 ml of HCl. Obtained g (11% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow solid. LCMS: [C 24 H 23 FN8O2S], desired mass 506.1, measured mass = 507.0 [M+H + ]. 1 H NMR(300MHz,CDCl3)δ9.50(d,J=10.2Hz,1H),8.69(d,J=12.7Hz,1H),8.36(s,1H),8 .22(s,1H),8.04(d,J=4.6Hz,1H),7.02(d,J=4.8Hz,1H),3.64(s,8H),1.50(s,9H).

[0273] Step 3: To a solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (5.4 g, 8.00 mmol) in anhydrous DMSO (80.0 mL, 0.1 M) was added D-alaninamide hydrochloride (9.96 g, 80.0 mmol) and sodium bicarbonate (10.1 g, 120 mmol). The reaction mixture was stirred at 120° C. for 1 hour. The product was precipitated by adding ice. The suspension was stirred at room temperature for 15 minutes. The solid was collected by filtration and washed with water until the filtrate was colorless. The solid was dried in vacuo. The residue was purified by silica gel flash chromatography eluting with 0-6% MeOH in DCM to give 1.36 g (30% yield) of tert-butyl 4-[5-(4-{[(1R-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow solid. LCMS: C 27 H 30 N 10 Theoretical value of O3S is 574.2, and the measured value is m / z=575.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.3Hz,1H),8.64(d,J=2.3Hz,1H),8.52(s,1H),8.13(s,1H),7.83(d,J=4.8Hz,1H),7.77(s ,1H),7.23(s,1H),7.13(d,J=4.9Hz,1H),6.87(s,1H),4.27(s,1H),3.54(d,J=6.8Hz,8H),1.50(d,J=6.8Hz,3H),1.44(s,9H).

[0274] Step 4: To a solution of tert-butyl 4-[5-(4-{[(1R-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (1.36 g, 2.37 mmol) in anhydrous DCM (23.7 mL, 0.1 M) was added trifluoroacetic anhydride (1.49 g, 7.1 mmol) and anhydrous pyridine (1.53 mL, 18.9 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. The reaction was incomplete, so trifluoroacetic anhydride (0.049 g, 0.24 mmol) and anhydrous pyridine were added. HCl (0.05 mL, 0.63 mmol) was added and the mixture was stirred under argon at room temperature for 30 minutes. Saturated aqueous NaHCO3 was poured into the mixture, and the mixture was extracted with DCM to give 671 mg of crude product. The crude material was purified by silica gel flash chromatography eluting with 0-4% MeOH in DCM to give 0.33 g (24% yield) of tert-butyl 4-[5-(4-{[(1R)-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as an orange solid. LCMS: C 27 H 28 N 10 O2S theoretical value 556.2, actual value m / z = 557.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.88(d,J=2.3Hz,1H),8.83(d,J=6.9Hz,1H),8.68(d,J=2.3Hz,1H),8.64(s,1H),8.37(s,1H),7.8 8(d,J=4.8Hz,1H),7.15(d,J=4.8Hz,1H),5.04(t,J=6.9Hz,1H),3.55(d,J=7.5Hz,8H),1.78(d,J=6.9Hz,3H),1.44(s,9H).

[0275] Step 5: To a solution of tert-butyl 4-[5-(4-{[(1R)-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (0.97 g, 1.7 mmol) in anhydrous dichloromethane (34.8 mL, 0.05 M) was added trifluoroacetic acid (8 mL, 105 mmol) and anisole (0.381 mL, 3.48 mmol). The reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated and the residue was triturated four times with diethyl ether to give 790 mg of 7-(4-{[(1R)-1-cyanoethyl]amino}-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as the TFA salt. The salt was dissolved in 20 mL of a mixture of DCM / MeOH (9:1, v / v) and washed with 7% aqueous NaHCO3 (30 mL). The aqueous layer was extracted twice with 10% MeOH in DCM and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 0.562 g (63% yield) of the title compound as a yellow powder. LCMS: C 22 H 20 N 10 S, desired mass = 456.2, actual m / z = 457.1 [M+H] + , 1 H NMR(300MHz,DMSO-d6)δ8.90-8.80(m,2H),8.68(dJ=2.3Hz,1H),8.64(s,1H),8.37(s,1H),7.88(dJ=4.8H) z,1H),7.15(dJ=4.8Hz,1H),5.04(tJ=7.0Hz,1H),3.53(dJ=5.2Hz,4H),2.89(m,4H),1.78(dJ=6.9Hz,3H).

[0276] Intermediate AD: 7-[4-(methylamino)-5-[5-(piperidin-4-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3carbonitrile.

[0277] [ka]

[0278] Step 1: To a solution of 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (3.55 g, 17.69 mmol, 1 equiv.) and monomethyl 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (4.46 g, 19.46 mmol, 1.1 equiv.) in DMF (60 mL, 0.3 M), DIPEA (9.3 mL, 53.08 mmol, 3 equiv.) and HATU (8.1 g, 21.23 mmol, 1.2 equiv.) were added. The mixture was stirred at 25 °C overnight. The reaction mixture was quenched with ice / water (600 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , and concentrated under reduced pressure. The crude was purified by FC (DCM / MeOH, 0-10%) to give 6.44 g of tert-butyl 4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate (85% yield). LCMS: ESI(+)[MH] - =410.40. 1 H NMR (300 MHz, chloroform-d) δ 10.33 (s, 1H), 9.89 (s, 1H), 8.34 (s, 1H), 8.10 (d, J = 5.1 Hz, 1H), 6.66 (s, 1H), 3.95 (d, J = 13.2 Hz, 2H), 2.82 (d, J = 5.0 Hz, 5H), 2.47-2.36 (m, 1H), 1.71 (d, J = 12.5 Hz, 2H), 1.51-1.40 (m, 11H).

[0279] Step 2: tert-Butyl 4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate (3.4 g, 8.25 mmol, 1 equiv.) was dissolved in anhydrous THF (275 mL, 0.03 M) under argon. The solution was warmed to 40 °C, and P2S5 (2.75 mg, 12.38 mmol, 1.5 equiv.) was added portionwise with vigorous stirring. The resulting suspension was stirred at reflux for 1 h. Upon completion, the volatiles were evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and vigorously stirred with an aqueous solution of K2CO3. The aqueous layer was removed in a separatory funnel, and the organic solvent was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by FC (0-50% gradient of EtOAc in DCM) to give 1.82 g of tert-butyl 4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperidine-1-carboxylate (51% yield). LCMS: ESI(+) [M+H] + =410.4. 1 H NMR(300MHz,DMSO-d6)δ8.66(d,J=4.7Hz,1H),8.40(s,1H),6.84(s,1H),4.01(d,J=13.1Hz,2H),3.53- 3.36(m,1H),2.98(d,J=5.0Hz,5H),2.09(d,J=10.9Hz,2H),1.64(tt,J=12.0,6.5Hz,2H),1.42(s,9H).

[0280] Step 3: To a solution of tert-butyl 4-{5-[6-chloro-4-(methylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperidine-1-carboxylate (0.860 g, 2.097 mmol, 1.0 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.79 g, 2.936 mmol, 1.4 equiv) in anhydrous dioxane (7 mL, 0.3 M) was added potassium carbonate (0.87 g, 6.295 mmol, 3 equiv) dissolved in HO (0.35 mL, 6.0 M). The solution was degassed with argon for 15 min, and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.43 g, 0.524 mmol, 0.25 equiv.) complexed with dichloromethane was added. The tube was sealed and stirred at 120 °C overnight. The reaction was filtered through a pad of Celite and washed with DCM and MeOH. The solvent was evaporated under reduced pressure, and the residue was purified by FC (5-50% ACN in DCM) to give 363 mg of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperidine-1-carboxylate (36% yield). LCMS: ESI (+) [M+H] + =517.44. 1 H NMR(300MHz,DMSO-d6)δ8.86(d,J=1.9Hz,1H),8.75(d,J=1.9Hz,1H),8.68(s,1H),8.65(s,1H),8.21(s,1H),7.89(d,J=4.8Hz,1H),7.13( d,J=4.8Hz,1H),4.03(d,J=12.2Hz,2H),3.10(d,J=4.9Hz,3H),3.06-2.86(m,2H),2.11(d,J=11.5Hz,2H),1.76-1.56(m,2H),1.43(s,9H).

[0281] Step 4: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperidine-1-carboxylate (650 mg, 1.26 mmol) in HFIP (26 mL, 0.06 M) was stirred at 140 °C under MW irradiation for 4 h. Volatiles were evaporated and the residue was co-evaporated with DCM three times. The crude material was subjected to short silica gel flash chromatography (5-30% MeOH in DCM) to afford 474 mg (85% yield) of the title compound. LCMS: ESI(+) [M+H] + =417.21. 1 H NMR(300MHz,DMSO-d6)δ8.86(d,J=2.2Hz,1H),8.76(d,J=2.2Hz,1H),8.70(s,1H),8.65(q,J=4.3Hz,1H),8.21(s,1H),7.89(d,J=4.8Hz ,1H),7.14(d,J=4.8Hz,1H),3.10(d,J=4.9Hz,3H),3.08-2.98(m,2H),2.71-2.58(m,2H),2.09-1.97(m,2H),1.66(qd,J=12.2,3.6Hz,2H).

[0282] Intermediate AE: 7-(5-(5-((1r,4r)-4-(methylamino)cyclohexyl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride.

[0283] [ka]

[0284] Step 1: To a solution of methyl 4,6-dichloronicotinate (71.6 g, 347 mmol, 1.00 equiv.) and tetrahydro-2H-pyran-4-amine (87.9 g, 869 mmol, 2.50 equiv.) in i-PrOH (700 mL) was added DIEA (157 g, 1.22 mol, 212 mL, 3.50 equiv.). The reaction mixture was maintained at 30° C. under N for 12 h. The reaction mixture was poured into HO (1.00 L) and then extracted with ethyl acetate (1.00 L). * 3). The combined organic layers were washed with brine (1.00 L). * The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate, gradient: 20 / 1 to 10 / 1 to 3 / 1) to give methyl 6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinate (43.0 g, 157 mmol, 45.4% yield, 99.4% purity) as a white solid. TLC R f =0.30 (3:1 petroleum ether / ethyl acetate). LCMS: m / z=271.1 (M+H) + . 1 H NMR(400MHz,CDCl3)δ8.68(s,1H),8.27(d,J=8.0Hz,1H),6.56(s,1H),4.01(t,J=3.8,12.0H z,2H),3.89(s,3H),3.63-3.53(m,3H),2.04-1.98(m,2H),1.64(m,J=4.2,10.2,13.8Hz,2H)

[0285] Step 2: To a solution of methyl 6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinate (49.0 g, 179 mmol, 99.4% purity, 1.00 equiv.) in EtOH (300 mL) was added NH2NH2·HO (85.6 g, 1.45 mol, 83.2 mL, 85.0% purity, 8.03 equiv.). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into HO (300 mL) and then ethyl acetate (300 mL) was added. * The combined organic layer was extracted with brine (600 mL *2), dried over Na2SO4, filtered, and concentrated to give 6-chloro-4-((tetrahydro-2H-pyra (45.0 g, 166 mmol, 92.4% yield, 100% purity) nicotinohydrazide was obtained as a white solid. LCMS: m / z = 271.1 (M+H). + . 1 H NMR(400MHz,DMSO)δ9.86(s,1H),8.39(d,J=7.8Hz,1H),8.26(s,1H),6.84(s,1H),4.49(brs,2H),3.82(td,J= 3.6,11.6Hz,2H),3.78-3.65(m,1H),3.47(dt,J=2.2,11.2Hz,2H),1.88(brd,J=11.6Hz,2H),1.48-1.27(m,2H)

[0286] Step 3: To a solution of 6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinohydrazide (15.0 g, 55.4 mmol, 100% pure, 1.00 equiv.) and (1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexane-1-carboxylic acid (15.6 g, 60.9 mmol, 1.10 equiv.) in DMF (150 mL) was added HOBT (8.98 g, 66.4 mmol, 1.2 equiv.), EDCI (12.7 g, 66.4 mmol, 1.20 equiv.), and DIEA (21.4 g, 166 mmol, 28.9 mL, 3.00 equiv.). The reaction mixture was stirred at 25 °C under N for 2 h. The reaction mixture was poured into HO (200 mL), followed by ethyl acetate (200 mL). * The combined organic layer was extracted with brine (600 mL * The mixture was washed with 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give tert-butyl ((1r,4r)-4-(2-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinoyl)hydrazine-1-carbonyl)cyclohexyl)(methyl)carbamate (10.0 g, 17.3 mmol, 31.3% yield, 88.4% purity) as a yellow solid. TLC Rf =0.30 (petroleum ether / ethyl acetate=0 / 1). LCMS: m / z=510.1 (M+H) + . 1 H NMR(400MHz,DMSO)δ10.37(s,1H),9.85(s,1H),8.39(s,1H),8.27(brd,J=7.8Hz,1H),6.90(s,1H),3.91-3.67(m,4H ),3.52-3.40(m,2H),2.67(s,3H),2.18(brs,1H),1.93-1.80(m,4H),1.71-1.44(m,6H),1.40(s,9H),1.38(brs,2H)

[0287] Step 4: To a solution of tert-butyl ((1r,4r)-4-(2-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinoyl)hydrazine-1-carbonyl)cyclohexyl)(methyl)carbamate (10.0 g, 17.3 mmol, 88.4% purity, 1.00 equiv.) in THF (100 mL) was added P2S5 (5.78 g, 26.0 mmol, 2.76 mL, 1.50 equiv.) at 30 °C, and then the mixture was stirred at 70 °C for 2 h. After completion of the reaction, the volatiles were evaporated. The crude residue was dissolved in DCM (150 mL) and washed by vigorously stirring with 15% aqueous K2CO3 solution (150 mL). The organic layer was washed with water (200 mL) and brine (400 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 25 / 1 to 10 / 1) to give tert-butyl ((1r,4r)-4-(5-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)(methyl)carbamate (6.00 g, 8.82 mmol, 50.9% yield, 74.7% purity) as a yellow solid. TLC R f =0.20 (petroleum ether / ethyl acetate=1 / 1). LCMS: m / z=508.2 (M+H) + . 1H NMR(400MHz,CDCl3)δ9.08(brd,J=7.4Hz,1H),8.35(s,1H),6.65(s,1H),4.03(td,J=3.8,12.0Hz,2H),3.75-3.64(m,1H), 3.63-3.55(m,2H),3.09(tt,J=3.6,11.8Hz,1H),2.78(s,3H),2.37-2.27(m,2H),2.11-2.01(m,2H),1.89(brdd,J=2.4,12. 2Hz, 2H), 1.82-1.62 (m, 7H), 1.48 (s, 9H)

[0288] Step 5: To a solution of tert-butyl ((1r,4r)-4-(5-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)(methyl)carbamate (6.00 g, 11.8 mmol, 1.00 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (4.13 g, 15.3 mmol, 1.30 equiv) in DME (60.0 mL) was added KPO (2.00 M, 11.8 mL, 2.00 equiv) and XPhos Pd G3 (999 mg, 1.18 mmol, 0.100 equiv) was added under N2, and the mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was poured into H2O (100 mL) and then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (200 mL * 2), dried over NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250 * 70 *10 μm; mobile phase: [hexane-EtOH (0.1% NH₃.HO)]; B%: 1% to 40%, 20 min), then concentrated by lyophilization to give tert-butyl ((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)(methyl)carbamate (2.00 g, 1.96 mmol, 16.7% yield, 60.6% purity) as a yellow solid. LCMS: m / z = 615.2 (M+H). +

[0289] Step 6: To a solution of tert-butyl ((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)(methyl)carbamate (2.00 g, 1.96 mmol, 60.6% purity, 1.00 equiv) in EtOAc (10.0 mL) was maintained at 25° C. under N for 15 min, and HCl / EtOAc (4.00 M, 489 μL, 1.00 equiv) was added. The reaction mixture was concentrated in vacuo. The residue was treated with EtOAc (10.0 mL) at 25° C. for 1 h, then filtered, and the filter cake was concentrated in vacuo. 7-(5-(5-((1r,4r)-4-(methylamino)cyclohexyl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (1.01 g, 1.67 mmol, 85.3% yield, 91.1% purity, HCl) was obtained as a yellow solid. LCMS: m / z=515.1 (M+H). + . 1H NMR:(400MHz,MeOD)δ8.80-8.76(m,2H),8.71(d,J=2.0Hz,1H),8.16(d,J=5.2Hz,1H),8.0 0(s,1H),7.25(d,J=5.2Hz,1H),4.42-4.26(m,1H),4.04(td,J=3.8,12.0Hz,2H),3.78-3.6 9(m,2H),3.43-3.32(m,2H),3.20(tt,J=3.6,11.8Hz,1H),2.75(s,3H),2.49-2.40(m,2H) ,2.34(brd,J=10.4Hz,2H),2.20(brd,J=12.2Hz,2H),1.88-1.77(m,4H),1.71-1.62(m,2H)

[0290] Intermediate AF: 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0291] [ka]

[0292] Step 1: To a stirred solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (29.4 g, 138.49 mmol, 1.0 equiv.) in THF (462 mL, 0.3 M), TEA (57.9 mL, 3.0 equiv.) and 1,1′-thiocarbonyldiimidazole (29.61 g, 1.2 equiv.) were added at room temperature, and the reaction mixture was stirred for 2 h. The solution was then transferred dropwise to a solution of hydrazine monohydrate (20.80 g, 3 equiv.) in THF (130 mL). Completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (500 mL), and the aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was resuspended in water (600 mL) and filtered off. It was then washed with water to remove the imidazole by-product, yielding 35 g (88%) of tert-butyl 3-(aminocarbamothioyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a light pink solid. LCMS: [C 12 H 22 N4O2S], desired mass = 286.4, measured mass = 287.3 [M+H + ]. 1 H NMR (300MHz, DMSO-d6): δ9.05(s,1H),4.76(s,2H),4.40-3.98(m,4H),3.08-2.84(m,2H),1.91-1.70(m,2H),1.57(d,J=7.2Hz,2H),1.41(s,9H).

[0293] Step 2: To a solution of starting 4,6-dichloronicotinic acid (23.89 g, 124.45 mmol, 1.2 equiv) in dry DCM (345 mL, 0.3 M) in a dry atmosphere, TEA (17.35 mL, 124.45 mmol, 1.2 equiv) was added and the solution was cooled to −15° C. Isobutyl-chloroformate (17.0 g, 124.45 mmol, 1.2 equiv) was added dropwise while maintaining the temperature at −15° C. The solution was maintained at −15° C. for 1 hour. Then, at this temperature, tert-butyl 3-(aminocarbamothioyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0 g, 103.71 mmol, 1 equiv) was added in portions and the reaction was allowed to warm to 25° C. overnight. Upon completion, the solution was treated with solid NaHCO (pH = 8.0) and extracted with 3 x 500 mL of DCM. The combined organic layers were dried over NaSO, filtered, and evaporated to dryness. The crude residue was triturated three times with hexane to give 37.5 g (79%) of tert-butyl 3-{[(4,6-dichloropyridin-3-yl)formohydrazide]methanethioyl}-3,8-diazabiphenyl. Cyclo[3.2.1]octane-8-carboxylate was obtained as a pale yellow solid, which was used further without purification. LCMS: [C 18 H 23 Cl2N5O3S], desired mass = 460.34, observed mass = 459.9 [MH - ]. 1 H NMR (300MHz, CDCl3): δ10.63(s,1H),8.88(s,1H),8.68(d,J=19.5Hz,1H),7.51(s,1H),4.38 (s,4H),3.47-3.27(m,2H),2.13-1.93(m,2H),1.81(t,J=6.9Hz,2H),1.50(d,J=3.4Hz,9H).

[0294] Step 3: tert-Butyl 3-{[(4,6-dichloropyridin-3-yl)formohydrazide]methanethioyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.5 g, 81.46 mmol, 1 equiv.) was dissolved in HSO (272 mL, 0.3 M) and the solution was stirred at room temperature overnight. The mixture was poured onto ice with stirring, and KCO was added until the pH was approximately 10. The KSO was filtered off and rinsed with DCM. The layers were separated, and the aqueous layer was further extracted with DCM (3 x 500 mL). The combined organic layers were washed with brine (1 x 500 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a crude product which was triturated with hexanes to give 19.6 g (70%) of 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane as a pale yellow solid. LCMS: [C 13 H 13 Cl2N5S], desired mass = 341.0, observed mass = 341.8 [M+H + ]. 1 H NMR (300MHz, CDCl3): δ9.14(s,1H),7.49(s,1H),3.72(dd,J=9.1,3.1Hz,4H),3.47(dd,J=12.2,2.8Hz,2H),1.91(d,J=2.1Hz,5H).

[0295] Step 4: A solution of 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane (19.6 g, 57.27 mmol, 1 equiv.) was dissolved in DCM (115 mL, 0.5 M), TEA (9.58 mL, 68.72 mmol, 1.2 equiv.) was added, and the mixture was stirred for 5 min. BocO (15 g, 68.72 mmol, 1.2 equiv.) was then added, and the solution was stirred until complete (2 h). The solution was evaporated to dryness under reduced pressure. The crude material was then triturated with hexanes (3 x 300 mL) to give 21 g (83% yield) of tert-butyl 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. LCMS: [C 18 H 21 Cl2N5O2S], desired mass = 441.0, measured mass = 441.9[M+H + ]. 1 H NMR (300MHz, CDCl3): δ9.14(s,1H),7.50(s,1H),4.42(s,2H),3.54(s,4H),2.16-2.00(m,2H),1.87(d,J=7.4Hz,2H),1.52(s,9H).

[0296] Step 5: A solution of tert-butyl 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 2.94 mmol, 1.0 equiv), (S)-3-aminotetrahydrofuran hydrochloride (2.18 g, 17.63 mmol, 6.0 equiv), anhydrous potassium carbonate (3.24 g, 23.51 mmol, 8.0 equiv) and DIPEA (2.56 mL, 14.69 mmol, 5.0 equiv) in anhydrous ACN (30 mL, 0.1 M) and DMF (3 mL, 1 M) was stirred at 80° C. overnight. All volatiles were then removed under reduced pressure and the crude material was purified by silica gel flash chromatography eluting with dichloromethane / acetonitrile to afford 1.0 g (62% yield) of tert-butyl 3-(5-(6-chloro-4-(((S)-tetrahydrofuran-3-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white crystalline product. I(+)[M+H] + =494.0. 1 H NMR(300MHz,DMSO-d6)d:8.87(d,J=7.0Hz,1H),8.22(s,1H),6.90(s,1H),4.38(m,1H),4.27(m,2H),3.94 -3.72(m,3H),3.64(m,3H),3.34(m,2H),2.41-2.26(m,1H),1.91(m,2H),1.86-1.68(m,3H),1.43(s,9H).

[0297] Step 6: tert-Butyl 3-(5-(6-chloro-4-(((S)-tetrahydrofuran-3-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 1.82 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo-[1,2-b]pyridazine-3-carbonitrile (0.709 g, 2.556 mmol, 1.4 equiv), KPO (0.775 g, 3.651 mmol, 2.0 equiv) and XPhos Pd G3 (0.155 g, 0.18 mmol, 0.1 equiv) was suspended in 1,2-dimethoxyethane (26.08 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred at 120 °C overnight. The crude material was purified by silica gel flash chromatography eluting with dichloromethane / 2-propanol to afford 0.7 g (56% yield) of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. ESI(+) [M+H] + =600.47. 1 H NMR(300MHz,DMSO-d6)δ:8.82(d,J=2.2Hz,1H),8.76-8.68(m,2H),8.49(s ,1H),8.18(s,1H),7.83(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),4.30(d,J= 11.2Hz,3H),4.08-3.99(m,1H),3.93-3.78(m,2H),3.70(t,J=11.8Hz,3H) ,2.49-2.38(m,3H),1.98-1.85(m,3H),1.75(d,J=7.3Hz,2H),1.44(s,9H).

[0298] Step 7: To a solution of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.7 g, 1.0 mmol, 1.0 equiv) in anhydrous dichloromethane (3.5 mL, 0.3 M) was added trifluoroacetic acid (1.5 mL, 20.5 mmol, 20 equiv) and the resulting mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure and conversion to the free amine, the crude was purified by silica gel flash chromatography eluting with dichloromethane / methanol to give 0.34 g (62% yield) of 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid.

[0299] LCMS: ESI(+)[M+H] + =500.18. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.74(d,J=2.3Hz,2H),8.49(s,1H),8.19(s,1H),7.84(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),4. 35(m,1H),4.06(m,1H),3.95-3.79(m,2H),3.72(m,1H),3.55(m,3H),3.3 1-3.27(m,2H),2.49-2.38(m,2H),1.99-1.87(m,1H),1.80-1.65(m,4H).

[0300] Intermediate AG: 7-[5-(5-{2,7-diazaspiro[3.5]nonan-2-yl} -1,3,4-thiadiazol-2-yl)-4-(oxan-4-ylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0301] [ka]

[0302] Synthesized according to the same procedure as Intermediate T, except using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate. LCMS: ESI(+) [M+H] + =528.5. 1 H NMR (500MHz, methanol-d4) δ8.78(d,J=2.4Hz,1H),8.70(d,J=2.3Hz,1H),8.56(d,J=2.3Hz,1H),8.13(t,J=3.3Hz,1H),7.94(s,1H),7.30-7.09(m,2H) ),4.31(s,1H),4.13(d,J=2.2Hz,4H),4.11-3.97(m,3H),3.74(t,J=11.1 Hz,2H),3.26(s,5H),2.19(q,J=9.8,6.5Hz,6H),1.78(d,J=11.5Hz,2H).

[0303] Intermediate AH: 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)-4-(ethylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0304] [ka]

[0305] Step 1: A solution of tert-butyl 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.44 g, 0.10 mmol, 1.0 equiv), ethylamine solution (5 mL, 1.0 mmol, 10.0 equiv) in anhydrous acetonitrile (23 mL, 0.1 M) and DMF (2.5 mL, 1 M) was stirred at 80° C. for 21 h. All volatiles were then removed under reduced pressure, and the crude material was purified by silica gel flash chromatography eluting with dichloromethane / acetonitrile to give 0.44 g (98% yield) of tert-butyl 3-{5-[6-chloro-4-(ethylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white crystalline product. ESI(+)[M+H] + =451.9. 1 H NMR(300MHz,DMSO-d6),d:8.59(t,J=5.4Hz,1H),8.19(s,1H),6.80(s,1H),4.27(s, 2H), 3.65 (m, 2H), 3.30 (m, 4H), 1.91 (m, 2H), 1.73 (m, 2H), 1.43 (s, 9H), 1.25 (t, 3H).

[0306] Step 2: tert-Butyl 3-{5-[6-chloro-4-(ethylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.44 g, 0.98 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.387 g, 1.4 mmol, 1.4 equiv), KPO (0.414 g, 1.951 mmol, 2.0 equiv), and XPhos Pd G (0.083 g, 0.1 mmol, 0.1 equiv) were suspended in 1,2-dimethoxyethane (13.94 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred at 120° C. overnight. The crude material was purified by silica gel flash chromatography eluting with dichloromethane / 2-propanol (9:1) to give 0.31 g (51% yield) of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. ESI(+)[M+H] + =559.0. 1 H NMR(300MHz,DMSO-d6),δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.49(t,J=10.2Hz,2H),8.16(s,1H),7.85(d,J=4.8Hz,1H),7.11(d,J =4.8Hz,1H),4.29(s,2H),3.68(d,J=11.2Hz,2H),3.50-3.37(m,4H),1.93(s,2H),1.76(d,J=7.4Hz,2H),1.45(s,9H),1.34(t,J=7.1Hz,3H).

[0307] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.31 g, 0.5 mmol, 1.0 equiv) in anhydrous dichloromethane (5.0 mL, 0.1 M) was added trifluoroacetic acid (0.8 mL, 10.0 mmol, 20.0 equiv) and the resulting mixture was stirred at room temperature for 1 hour. After evaporation of all volatiles, the crude residue was triturated with anhydrous diethyl ether to give 0.21 g (89% yield) of 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)-4-(ethylamino)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS: ESI(+) [M+H] + =458.09. 1 H NMR(300MHz,DMSO-d6)δ:9.19(m,3H),8.95(d,J=2.2Hz,1H),8.82(d,J=2.2Hz,1H),8.57(s,1H),8.11-7.95(m,2H),7 .21(d,J=5.0Hz,1H),4.23(m,2H),3.95-3.82(m,2H),3.65-3.60(brm,4H),2.10-1.91(m,4H),1.34(t,J=7.1Hz,3H).

[0308] Intermediate AI: 7-(4-{[(3S)-oxolan-3-yl]amino}-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0309] [ka]

[0310] Step 1: To a solution of tert-butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (1.4 g, 1 equiv.) in DMF (3.3 mL, 1 M) and t-BuOH (11 mL, 0.3 M), DIPEA (8.7 mL, 15 equiv.) and (S)-3-aminotetrahydrofuran hydrochloride (4.12 g, 10 equiv.) were added. The pressure vessel was sealed, and the mixture was stirred at 100 °C overnight. The solvent was evaporated under reduced pressure. The crude was then dissolved in DCM and washed with HO, NaHCO, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 420 mg (24% yield) of tert-butyl 4-[5-(6-chloro-4-{[(3S)-oxolan-3-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate. ESI(+)[M+H] + =467.26.

[0311] 1 H NMR(300MHz,DMSO-d6)δ8.86(d,J=6.9Hz,1H),8.22(s,1H),6.91(s,1H),4.46-4.31(m,1H),3.96-3.69(m,3H) ,3.64(dd,J=9.3,2.5Hz,1H),3.59-3.44(m,8H),2.45-2.25(m,1H),1.81(dd,J=8.0,5.0Hz,1H),1.43(s,9H).

[0312] Step 2: tert-Butyl 4-[5-(6-chloro-4-{[(3S)-oxolan-3-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (420 mg, 0.9 mmol, 1 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.267 g, 1.26 mmol, 1.4 equiv), KPO (0.382 g, 1.8 mmol, 2 equiv) and XPhos Pd G (3.36 g, 0.063 mmol, 0.07 equiv) were suspended in DME (13 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred at 120° C. overnight. The crude material was purified by silica gel flash chromatography eluting with DCM / acetonitrile and DCM / i-PrOH to afford 225 mg (53% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(3S)-oxolan-3-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow solid. ESI(+)[M+H] + =575.42. 1 H NMR(300MHz,DMSO-d6)δ8.85(s,1H),8.80-8.69(m,2H),8.52(s,1H),8.22(s,1H),7.85(d,J=5.0Hz,1H),7.12(d,J=4.6Hz,1H), 4.43-4.27(m,1H),4.10-4.00(m,1H),4.00-3.79(m,2H),3.79-3.70(m,1H),3.59-3.48(m,8H),2.01-1.87(m,1H),1.44(s,9H).

[0313] Step 3: To a solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(3S)-oxolan-3-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (225 mg, 0.384 mmol, 1 equiv.) in DCM (3 mL), TFA (2 mL) was added and the mixture was stirred at room temperature. After 1.5 h, the solvent was evaporated under reduced pressure. The crude was suspended in EtO and sonicated for 30 min. The solid was filtered off to give 160 mg (81% yield) of 7-(4-{[(3S)-oxolan-3-yl]amino}-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (TFA salt) as a yellow solid. LCMS: ESI(+) [M+H] + =473.98. 1 H NMR(300MHz,DMSO-d6)δ9.28(s,1H),9.03-8.88(m,3H),8.84(d,J=1.9Hz,1H),8.61(s,1H),8.14(s,1H),7.99(d,J=4.8Hz ,1H),7.20(d,J=4.9Hz,1H),4.53(s,1H),4.04(dd,J=9.5,5.4Hz,2H),3.93-3.80(m,7H),3.32(s,4H),2.02-1.89(s,1H).

[0314] Intermediate AJ: 7-(4-{[(3R)-oxolan-3-yl]amino}-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0315] [ka]

[0316] Step 1: A solution of tert-butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (1.74 g, 4.18 mmol, 1 equiv.) was dissolved in DMF (4 mL, 1 M) and t-BuOH (14 mL, 0.3 M). DIPEA (9 mL, 15 equiv.) and (R)-3-aminotetrahydrofuran (3.6 g, 10 equiv.) were then added. The pressure vessel was sealed, and the mixture was stirred at 100° C. overnight. The solvent was evaporated under reduced pressure. The crude was then dissolved in DCM and washed with HO, NaHCO, brine, and the organic phase was dried over NaSO, filtered, and evaporated under reduced pressure to give 1.7 g (79% yield) of tert-butyl 4-[5-(6-chloro-4-{[(3R)-oxolan-3-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate. LCMS: ESI(+) [M+H] + =467.27. 1 H NMR(300MHz,DMSO-d6)δ8.86(d,J=6.9Hz,1H),8.22(s,1H),6.91(s,1H),4.46-4.31(m,1H),3.96-3.69(m,3H) ,3.64(dd,J=9.3,2.5Hz,1H),3.59-3.44(m,8H),2.45-2.25(m,1H),1.81(dd,J=8.0,5.0Hz,1H),1.43(s,9H).

[0317] Step 2: tert-Butyl 4-[5-(6-chloro-4-{[(3R)-oxolane- [3-yl]amino{pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (1.7 g, 3.3 mmol, 1 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.36 g, 5.04 mmol, 1.4 equiv.), KPO (1.53 g, 7.2 mmol, 2 equiv.), and XPhos Pd G (0.213 g, 0.252 mmol, 0.07 equiv.) were suspended in DME (52 mL, 0.07 M). The mixture was degassed with argon for 20 min and stirred at 120 °C overnight. The crude material was purified by silica gel flash chromatography eluting with DCM / acetonitrile and DCM / i-PrOH to afford 670 mg (33% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(3R)-oxolan-3-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow solid. ESI(+) [M+H] + =574.42. 1 H NMR(300MHz,DMSO-d6)δ8.84(d,J=2.2Hz,1H),8.76(d,J=2.1Hz,1H),8.51(s,1H),8.21(s,1H),7.85(d,J=4. 8Hz, 1H), 7.12 (d, J=4.8Hz, 1H), 4.35 (s, 2H), 4.12-3.71 (m, 6H), 3.61-3.42 (m, 8H), 1.93 (s, 1H), 1.44 (s, 9H).

[0318] Step 3: tert-Butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(3R)-oxolan-3-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (670 mg, 1.11 mmol, 1.0 equiv) was dissolved in DCM (10 mL, 0.3 M) and the solution was cooled to 0 °C. TFA (7.6 g, 10 equiv) was then added dropwise and the mixture was stirred at room temperature for 3 h. Upon completion, the mixture was evaporated to dryness. The crude material was suspended in EtO and sonicated for 30 min. The solid was filtered to give 380 mg (65% yield) of 7-(4-{[(3R)-oxolan-3-yl]amino}-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile

[0319] (TFA salt) was obtained as a yellow solid. LCMS: ESI(+)[M+H] + =474.43. 1 H NMR(300MHz,DMSO-d6):δ8.96-8.83(m,4H),8.80(d,J=2.1Hz,1H),8.58(s,1H),8.22(s,1H),7.90(d,J=4.8Hz,1H),7. 16(d,J=4.9Hz,1H),4.43(s,1H),4.06(dd,J=9.3,5.3Hz,1H),3.95-3.72(m,8H),3.35-3.21(m,4H),2.01-1.86(m,1H).

[0320] Intermediate AK: 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(((R)-tetrahydrofuran-3-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0321] [ka]

[0322] Step 1: A solution of tert-butyl 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 2.26 mmol, 1.0 equiv), (R)-3-aminotetrahydrofuran (1.38 g, 15.83 mmol, 7 equiv), anhydrous potassium carbonate (2.5 g, 18.08 mmol, 8.0 equiv) and DIPEA (1.5 mL, 11.30 mmol, 8.0 equiv) in anhydrous acetonitrile (23 mL, 0.1 M) and DMF (2.5 mL, 1 M) was stirred at 80° C. overnight. All volatiles were then evaporated under reduced pressure and the crude material was purified by silica gel flash chromatography eluting with dichloromethane / acetonitrile to afford 1.1 g (94% yield) of tert-butyl 3-(5-(6-chloro-4-(((R)-tetrahydrofuran-3-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white crystalline product. LCMS: ESI(+) [M+H] + =493.9. 1 H NMR(300MHz,DMSO-d6),d:8.87(d,J=7.0Hz,1H),8.22(s,1H),6.90(s,1H),4.37(m,1H),4.27(m,2H) ),3.87(m,3H),3.65(m,3H),3.34(m,2H),2.39-2.26(m,1H),1.91(m,2H),1.77(m,3H),1.43(s,9H).

[0323] Step 2: tert-Butyl 3-(5-(6-chloro-4-(((R)-tetrahydrofuran-3-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.1 g, 2.12 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.35 g, 5.27 mmol, 1.4 equiv), KPO (1.0 g, 5.1 mmol, 2.0 equiv) and XPhos Pd G3 (0.220 g, 0.25 mmol, 0.1 equiv) was suspended in 1,2-dimethoxyethane (36 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred at 120° C. overnight. The crude material was purified by silica gel flash chromatography eluting with DCM / 2-propanol to afford 0.65 g (46% yield) of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((R)-tetrahydrofuran-3-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS: ESI(+) [M+H] + =574.42. H NMR(300MHz,DMSO-d6)δ8.84(d,J=2.2Hz,1H),8.76(d,J=2.1Hz,1H),8.51(s,1H),8.21(s,1H),7.85(d,J=4. 8Hz, 1H), 7.12 (d, J=4.8Hz, 1H), 4.35 (s, 2H), 4.12-3.71 (m, 6H), 3.61-3.42 (m, 8H), 1.93 (s, 1H), 1.44 (s, 9H).

[0324] Step 3: To a solution of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((R)-tetrahydrofuran-3-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.64 g, 0.96 mmol, 1.0 equiv) in dichloromethane (3.5 mL, 0.3 M) was added trifluoroacetic acid (1.47 mL, 19.21 mmol, 20.0 equiv) and the resulting mixture was stirred at room temperature for 3 hours. After evaporation of all volatiles under reduced pressure and conversion to the free amine, the crude was purified by silica gel flash chromatography eluting with dichloromethane / methanol to give 0.1 g (19% yield) of 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(((R)- Tetrahydrofuran-3-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile was obtained as a yellow solid. LCMS: ESI(+) [M+H] + =500.13. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.81-8.71(m,2H),8.49(s,1H),8.19(s,1H),7.84(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),4.34(s,1 H),4.10-4.02(m,1H),3.95-3.79(m,2H),3.72(m,1H),3.52(d,J=9.5Hz,4 H),3.42(s,1H),2.42(s,2H),1.93(d,J=8.3Hz,1H),1.71(d,J=5.7Hz,4H).

[0325] Intermediate AL: 7-[4-(cyclopropylamino)-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile bis(trifluoroacetate)

[0326] [ka]

[0327] Step 1: A solution of tert-butyl 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8 carboxylate (1.0 g, 2.24 mmol, 1.0 equiv.), cyclopropylamine (1.0 g, 17.514 mmol, 7.83 equiv.) in anhydrous acetonitrile (8 mL, 0.3 M) was stirred overnight at 80° C. UPLC control was applied. All volatiles were then removed under reduced pressure and the crude material was purified by silica gel flash chromatography eluting with dichloromethane / acetonitrile to afford 1.0 g (87% yield) of tert-butyl 3-{5-[6-chloro-4-(cyclopropylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white crystalline product. LCMS: ESI(+) [M+H] + =463.9. 1 H NMR(300MHz,DMSO-d6)d:8.73(m,1H),8.22(s,1H),7.05(s,1H),4.27(m,2H),3.65(d,J=11.4Hz, 2H), 2.68 (s, 1H), 2.58 (s, 2H), 1.92 (m, 2H), 1.73 (m, 2H), 1.44 (s, 9H), 0.90 (m, 2H), 0.58 (m, 2H).

[0328] Step 2: tert-Butyl 3-{5-[6-chloro-4-(cyclopropylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}-3,8-diazabicyclo-[3.2.1]-octane-8-carboxylate (1.0 g, 1.9 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.77 g, 2.72 mmol, 1.4 equiv), KPO (0.825 g, 3.89 mmol, 2.0 equiv), and XPhos Pd G (0.165 g, 0.194 mmol, 0.1 equiv) were suspended in 1,2-dimethoxyethane (28 mL, 0.07 M). The mixture was degassed with argon for 20 min and stirred overnight at 115° C. The crude material was purified by silica gel flash chromatography eluting with dichloromethane / 2-propanol (9:1) to give 0.31 g tert-Butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a yellow solid (51% yield). ESI(+) [M+H] + =571.1. 1 H NMR(300MHz,DMSO-d6)δ:8.84(d,J=2.2Hz,1H),8.76(d,J=2.2Hz,1H),8.66(d,J=4.0Hz,2H),8.49(s,1H),7.87(d,J=4.8Hz,1H),7.13(d,J= 4.8Hz,1H),4.28(s,2H),3.67(d,J=11.5Hz,2H),3.37(m,2H),2.74(m, 1H),1.93(m,2H),1.74(m,2H),1.44(s,9H),1.00(m,2H),0.64(m,2H).

[0329] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.6 g, 0.85 mmol, 1.0 equiv.) in anhydrous dichloromethane (8.5 mL, 0.1 M), trifluoroacetic acid (1.3 mL, 17 mmol, 20.0 equiv.) was added and the resulting mixture was stirred at room temperature for 1 h. UPLC control was applied. After evaporation of all volatiles, the crude residue was triturated with anhydrous diethyl ether to give 0.6 g (99% yield) of 7-[4-(cyclopropylamino)-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl]pyrrole[1,2-b]pyridazine-3-carbonitrile bis(trifluoroacetate) as a yellow solid. LCMS: ESI(+) [M+H] + =470.194. 1 H NMR(300MHz,DMSO-d6)δ:9.36(m,2H),9.17(s,1H),8.94(s,1H),8.85(s,1H),8.59(d,J=6.9Hz,2H),8.00(d,J=4.9Hz,1H),7.21(d,J =4.9Hz,1H),4.24(s,2H),3.87(d,J=12.1Hz,2H),3.63(d,J=12.1Hz,2H),2.86(s,1H),2.13-1.83(m,4H),1.07(m,2H),0.72(m,2H).

[0330] Intermediate AM: 7-[4-(cyclobutylamino)-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile trifluoroacetate.

[0331] [ka]

[0332] Step 1: A solution of tert-butyl 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.1 g, 2.5 mmol, 1.0 equiv) and cyclobutylamine (1.751 g, 24.618 mmol, 10.0 equiv) in dry acetonitrile (8 mL, 0.3 M) was heated at 80 °C overnight. All volatiles were removed under reduced pressure and the crude material was purified by silica gel flash chromatography eluting with dichloromethane / acetonitrile to give 1.05 g (81% yield) of tert-butyl 3-{5-[6 -chloro-4-(cyclobutylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as an off-white crystalline product. ESI(+) [M+H] + =479.0. 1 H NMR(300MHz,DMSO-d6)d:8.82(d,J=6.2Hz,1H),8.20(s,1H),6.68(s,1H),4.27(m,2H),4.1 5(m,1H),3.66(d,J=11.1Hz,2H),2.44(s,3H),1.90(s,4H),1.85-1.66(m,5H),1.43(s,9H).

[0333] Step 2: tert-Butyl 3-{5-[6-chloro-4-(cyclobutylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}-3,8-diazabicyclo[3.2.1]-octane-8-carboxylate (1.0 g, 1.992 mmol, 1.0 equiv), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.79 g, 2.788 mmol, 1.4 equiv), KPO (0.845 g, 3.983 mmol, 2.0 equiv) and XPhos Pd G (0.169 g, 0.199 mmol, 0.1 equiv) were suspended in 1,2-dimethoxyethane (8 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred at 117° C. overnight. The crude material was purified by silica gel flash chromatography eluting with dichloromethane / 2-propanol to give 0.47 g (38% yield) of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclobutylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. ESI(+)[M+H] + =584.65. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.78(d,J=2.2Hz,1H),8.68(d,J=5.2Hz,1H),8.48(s,1H),8.10(s,1H),7.84(d,J=4.8Hz,1H),7.11( d,J=4.8Hz,1H),4.28(s,2H),4.22-4.10(m,1H),3.68(d,J=11.3Hz,2H),2 .68-2.52(m,5H),2.05-1.84(m,6H),1.76(d,J=11.3Hz,2H),1.44(s,9H).

[0334] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclobutylamino)-pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.47 g, 0.76 mmol, 1.0 equiv) in anhydrous dichloromethane (8.5 mL, 0.1 M) was added trifluoroacetic acid (1.7 mL, 15 mmol, 20.0 equiv) and the resulting mixture was stirred at room temperature for 1 hour. All volatiles were evaporated and the crude residue was triturated with anhydrous diethyl ether to give 0.35 g (91% yield) of 7-[4-(cyclobutylamino)-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile trifluoroacetate as a yellow solid. LCMS: ESI(+) [M+H] + =484.24. 1 H NMR(300MHz,DMSO-d6)δ:9.27(brm,3H),8.94(d,J=2.2Hz,1H),8.86(d,J=2.2Hz,1H),8.59(s,1H),7.99(d,J=5.8Hz,2H),7.20( d,J=4.9Hz,1H),4.32(m,2H),4.23(s,2H),3.88(d,J=12.9Hz,2H),3.69-3.58(m,2H),2.61(d,J=5.3Hz,2H),2.14-1.82(m,8H).

[0335] Intermediate AN: 7-{4-[(1-cyanocyclopropyl)amino]-5-{5-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,4 -thiadiazol-2-yl}pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0336] [ka]

[0337] Step 1: tert-Butyl 3-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 11.30 mmol, 1 equiv.), KF (755 mg, 12.99 mmol, 1.15 equiv.), and 18-crown-6 ether (1.49 g, 5.65 mmol, 0.5 equiv.) were dissolved in anhydrous dimethyl sulfoxide (41 mL), and the reaction mixture was stirred at 105 °C overnight. The reaction mixture was then diluted with water (50 mL) and extracted with DCM (3 × 100 mL). The DCM layer was washed twice with water and then with brine. The organic layer was dried over NaSO and filtered. The solvent was then removed in vacuo. The crude product, 8.3 g, was purified by FC using a gradient of 0-100% EtOAc in hexane to give 4.1 g of tert-butyl 3-[5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid. LCMS: [C 18 H 21 ClFN5O2S], desired mass=425.9, measured mass=425.9[M+H + ]. 1 H NMR (300 MHz, DMSO-d): δ 9.04 (d, J = 10.0 Hz, 1H), 7.90 (d, J = 10.4 Hz, 1H), 4.28 (s, 2H), 3.77-3.60 (m, 2H), 3.36-3.33 (m, 1H, combined with residual solvent peaks), 3.39 (d, J = 2.3 Hz, 1H), 1.91 (d, J = 7.1 Hz, 2H), 1.74 (d, J = 7.4 Hz, 2H), 1.44 (s, 9H).

[0338] Step 2: To a solution of tert-butyl 3-[5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.4 g, 12.68 mmol, 1.0 equiv.) in dimethoxyethane (181 mL, 0.07 M) in a glass reactor, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (4.09 g, 15.21 mmol, 1.2 equiv.) was added. The reactor was evacuated and filled with argon three times. Xphos Pd G3 (751 mg, 0.89 mmol, 0.07 equiv.) and potassium phosphate tribasic (5.38 g, 25.357 mmol, 2.0 equiv.) were added. After evacuation-backfilling three times, the reactor was sealed and the mixture was stirred at 120 °C overnight. After the reaction was complete, the mixture was cooled to room temperature and diluted with DCM (200 mL). ) and concentrated. The residue was purified by FC using a gradient of ACN in DCM (0-100%) to give 4.15 g (62% yield) of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. LCMS: [C 26 H25FN8O2S], desired mass=532.6, measured mass=533.1[M+H + ].

[0339] 1 H NMR (300MHz, CDCl3): δ9.52(d,J=10.2Hz,1H),8.71(d,J=12.9Hz,1H),8.39(d,J=2.2Hz,1H),8.25(d,J=2.3Hz,1H),8.06(d,J=4.9 Hz,1H),7.04(d,J=4.9Hz,1H),4.43(s,2H),3.64(d,J=56.8Hz,4H),2.06(q,J=8.4,6.9Hz,2H),1.88(d,J=7.4Hz,2H),1.52(s,9H).

[0340] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 0.76 mmol) and 1-aminocyclopropane-1-carbonitrile hydrochloride (2.5 g, 21 mmol) in anhydrous DMSO (10 mL, 0.1 M) was added anhydrous DIPEA (10 mL, 57 mmol). The reaction mixture was stirred overnight at 130 °C under an Ar atmosphere. The reaction mixture was cooled to room temperature and diluted with CHCl. ​​The organic layer was washed with brine (3 times). The organic layer was dried over MgSO and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with CHCN / CHCl (gradient of 0% to 30% CHCN) to afford 164 mg (36% yield) of tert-butyl 3-(5-{4-[(1-cyanocyclopropyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS: [C 30 H 30 N 10 O2S], measured mass=594.70[M+H + ]. 1 H NMR(300MHz,DMSO-d6):δ9.03(s,1H),8.90-8.87(m,1H),8.86-8.83(m,2H),8.62(s,1H),7.92(d,J=4.8Hz,1H),7.16(d,J=4.8Hz,1 H),4.36-4.24(m,2H),3.78-3.60(m,2H),3.43-3.35(m,2H),1.96-1.81(m,4H),1.80-1.70(m,2H),1.58-1.47(m,2H),1.44(s,9H).

[0341] Step 4: To a solution of tert-butyl 3-(5-{4-[(1-cyanocyclopropyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (164 mg, 0.28 mmol) in anhydrous CHCl (2.8 mL, 0.1 M) was added TFA (0.40 mL, 5.6 mmol). The resulting mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure. The residue was triturated with anhydrous EtO to give 149 mg (quantitative yield) of 7-{4-[(1-cyanocyclopropyl)amino]-5-{5-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (TFA salt) as a yellow solid. LCMS: ESI(+) [M+H] + =495.16. 1 H NMR(300MHz,DMSO-d6):δ9.30-9.02(m,3H),8.92(d,J=2.3Hz,1H),8.88(d,J=2.3Hz,1H),8.86(s,1H),8.67(s,1H),7.95(d,J=4.8Hz,1H),7.19(d,J =4.8Hz,1H),4.30-4.15(m,2H),3.93-3.80(m,2H),3.68-3.53(m,2H),2.10-1.94(m,4H),1.95-1.83(m,2H),1.56-1.49(m,2H).

[0342] Intermediate AO: 7-{4-[(cyanomethyl)amino]-5-{5-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0343] [ka]

[0344] Step 1: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.62 mmol) and 2-aminoacetonitrile hydrochloride (918 mg, 9.9 mmol) in DMA / CHCN (6.5:1) (23 mL, 0.1 M) was added DIPEA (2.6 mL, 15 mmol). The reaction mixture was stirred overnight at 110 °C under an Ar atmosphere. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with CHCN / CHCl (gradient of 0% to 20% CHCN) to afford 250 mg (63% yield) of tert-butyl 3-(5-{4-[(cyanomethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS: [C 28 H 28 N 10 O2S], measured mass=569.10[M+H + ]. 1 H NMR(300MHz,DMSO-d6):δ8.90-8.78(m,2H),8.68(d,J=2.3Hz,1H),8.60(s,1H),8.30(s,1H),7.87(d,J=4.8Hz,1H),7.15(d,J=4.8Hz,1 H),4.69(d,J=6.1Hz,2H),4.34-4.22(m,2H),3.75-3.64(m,2H),3.43-3.35(m,2H),1.96-1.87(m,2H),1.81-1.65(m,2H),1.44(s,9H).

[0345] Step 2: To a solution of tert-butyl 3-(5-{4-[(cyanomethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.25 g, 0.44 mmol) in anhydrous CHCl (4.4 mL, 0.1 M) was added TFA (0.67 mL, 8.8 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was purified by preparative HPLC (CHCN / HO+0.1% HCOOH) to give 164 mg (75% yield) of 7-{4-[(cyanomethyl)amino]-5-{5-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,4-thiadiazol-2-yl}pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (TFA salt) as a yellow solid. LCMS: ESI(+) [M+H] + =469.39. 1 H NMR (300MHz, DMSO-d6): δ8.88(d,J=2.3Hz,1H),8.82(t,J=6.2Hz,1H),8.68(d,J=2.3Hz,1H),8.63(s,1H),8.31(s,1H),7.87(d,J=4 .8Hz,1H),7.15(d,J=4.8Hz,1H),4.70(d,J=6.2Hz,2H),4.08-3.98(m,2H),3.83-3.71(m,2H),3.59-3.46(m,2H),2.02-1.82(m,4H).

[0346] Intermediate AP: 7-[4-(cyclobutylamino)-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0347] [ka]

[0348] Step 1: In a pressure vessel, tert-butyl 4-(5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (1.2 g, 1 equiv.) was dissolved in DMF (3 mL, 1 M) and t-BuOH (9.5 mL, 0.3 M). DIPEA (7.4 mL, 15 equiv.) and cyclobutylamine (1.4 g, 7 equiv.) were then added. The pressure vessel was sealed, and the mixture was warmed to 80° C. overnight. The solvent was evaporated under reduced pressure, and the crude material was then dissolved in DCM, washed with HO, NaHCO, and brine, dried over NaSO, filtered, and evaporated under reduced pressure to give tert-butyl 4-{5-[6-chloro-4-(cyclobutylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (750 mg, 58%). LCMS: ESI(+) [M+H] + =451.30. 1 H NMR(300MHz,DMSO-d6)δ8.82(d,J=6.2Hz,1H),8.21(s,1H),6.69(s,1H),4.15(h,J=8.6 ,8.1Hz,1H),3.52(d,J=3.9Hz,8H),2.48-2.41(m,2H),1.99-1.72(m,4H),1.43(s,9H).

[0349] Step 2: tert-Butyl 4-{5-[6-chloro-4-(cyclobutylamino)pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (750 mg, 1.63 mmol, 1 equiv.), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (630 mg, 1.4 equiv.), KPO (709 mg, 2 equiv.), and XPhos Pd G3 (101.6 mg, 0.07 equiv.) were suspended in DME (25 mL, 0.07 M). The mixture was degassed with argon for 20 min and warmed to 120 °C overnight. The crude material was purified by FC (DCM / IPA 0-10%) to give tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclobutylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate as a yellow solid (444 mg, 48%). LCMS: ESI(+) [M+H] + =558.44. 1 H NMR (300 MHz, DMSO-d6) δ8. 83(d,J=2.3Hz,1H),8.78(d,J=2.3Hz,1H),8.68(d,J=5.1Hz,1H),8.49(s,1H),8.11(s,1H),7.84(d,J=4.8Hz,1H),7 .11(d,J=4.9Hz,1H),4.24-4.09(m,1H),3.60-3.46(m,8H),2.60(d,J=10.2Hz,2H),2.10-1.82(m,4H),1.44(s,9H).

[0350] Step 3: tert-Butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclobutylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (444 mg, 1 equiv.) was dissolved in DCM (5 mL), then TFA (2 mL) was added and the solution was stirred for 1.5 h. Upon completion, the mixture was evaporated to dryness, suspended in EtO, and sonicated for 30 min. The suspension was filtered to give 7-[4-(cyclobutylamino)-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as the TFA salt (477 mg, 87%). LCMS: ESI(+) [M+H] + =458.09. 1 H NMR(300MHz,DMSO-d6)δ9.17(s,1H),9.01(s,2H),8.92(d,J=2.2Hz,1H),8.85(d,J=2.2Hz,1H),8.58(s,1H),8.03(s,1H),7.96(d,J=4.9Hz,1H),7.1 8(d,J=4.9Hz,1H),4.30(dq,J=14.2,7.0Hz,1H),3.86-3.75(m,4H),3.33( s, 4H), 2.68-2.54 (m, 2H), 2.15-1.97 (m, 2H), 1.91 (dt, J=9.6, 5.5Hz, 2H).

[0351] Intermediate AQ: 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)-4-{[(2R)-1-methoxypropan-2-yl]amino}pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile. TFA salt

[0352] [ka]

[0353] Step 1: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (660 mg, 1.24 mmol, 1 equiv.) was suspended (R)-1-methoxypropan-2-amine (2.21 g, 24.78 mmol, 20 equiv.) in anhydrous DMSO (12.4 mL, 0.1 M). To this was added anhydrous DIPEA (12.1 mL, 68.16 mmol, 55 equiv.). The reaction mixture was heated to 120° C. overnight. The reaction was cooled to room temperature and quenched by the addition of water (100 mL). The solid was filtered off and washed with water (until the washings were colorless). The resulting solid was dissolved in EtOAc. The EtOAc layer was dried over Na2SO4 to remove traces of water, filtered, and evaporated to give 650 mg of crude material. The crude material was purified by FC using 0-100% ACN in DCM to give 296 mg of semi-pure product. Trituration with MTBE and ACN was attempted to remove an impurity (m / z=656; likely a doubly substituted Suzuki product) but was unsuccessful. The semi-pure product was therefore re-purified by RPFC using 5% to 95% ACN in water to give 250 mg (32% yield) of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(2R-1-methoxypropan-2-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS: [C 30 H 35 N9O3S], desired mass = 601.2, actual mass = 602.2 [M+H + ]. 1H NMR(300MHz,DMSO-d6):δ8.84(d,J=2.2Hz,1H),8.73-8.63(m,2H),8.49(s,1 H),8.24(s,1H),7.84(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),4.28(s,2H),4 .09-3.94(m,1H),3.74-3.62(m,2H),3.58-3.47(m,2H),3.39(s,1H),3.36(s ,4H),1.91(s,2H),1.76(d,J=7.5Hz,2H),1.44(s,9H),1.32(d,J=6.5Hz,3H).

[0354] Step 2: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(2R)-1-methoxypropan-2-yl]amino}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (254 mg, 0.41 mmol, 1.0 equiv.) in anhydrous DCM (3.6 mL, 0.23 M) was added TFA (0.83 mL, 7.28 mmol, 20 equiv.), and the resulting mixture was maintained at room temperature for 1 hour. Volatiles were removed by evaporation. The crude material was triturated with EtO (4 × 10 mL) to give 251 mg (98%) of 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)-4-{[(2R)-1-methoxypropan-2-yl]amino}pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (as the TFA salt) as a pale yellow solid. LCMS: [C 25 H 27 N9OS], desired mass = 501.2, measured mass = 502.2 [M+H + ]. 1H NMR (300MHz, DMSO-d6): δ9.35(s,2H),9.25(s,1H),8.94(d,J=2.2Hz,1H),8.80(d,J=2.2Hz,1H),8.59(s,1H),8.12(s,1H),8.00(d,J=4.9Hz,1 H),7.20(d,J=4.9Hz,1H),4.23(s,3H),3.94-3.81(m,2H),3.69-3.51(m,4H),3.36(s,3H),1.98(dd,J=11.8,8.3Hz,4H),1.33(d,J=6.5Hz,3H).

[0355] Intermediate AR: 7-[4-(tert-butylamino)-5-[5-(piperazin 1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0356] [ka]

[0357] Step 1: tert-Butyl 4-[5-(4,6-dichloropyridin-3-yl)-1,3,4-thiadiazole-2-] in dimethyl sulfoxide (35.31 mL, 0.1 M) To a suspension of tert-butyl 4-{5-[4-(tert-butylamino)-6-chloropyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (1.5 g, 3.531 mmol), tert-butylamine (7.45 mL, 70.89 mmol) and N,N-diisopropylethylamine (29.0 mL, 166.487 mmol) were added. The reaction mixture was stirred at 110° C. for 24 hours. After completion of the reaction, it was cooled to room temperature and quenched by the addition of ice. The formed precipitate was filtered off and dried under reduced pressure. The crude product was purified by silica gel flash chromatography using 0 to 100% EtOAc in hexane to give 810 mg (51% yield) of tert-butyl 4-{5-[4-(tert-butylamino)-6-chloropyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate as a white solid. LCMS: [C 20 H 29ClN6O2S], desired mass = 452.2, observed mass = 453.6 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.02 (s, 1H), 8.20 (s, 1H), 6.86 (s, 1H), 3.57-3.45 (m, 8H), 1.43 (d, J = 1.9Hz, 18H).

[0358] Step 2: Tert-butyl 4-{5-[4-(tert-butylamino)-6-chloropyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (0.88 g, 1.94 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.732 g, 2.72 mmol), potassium phosphate tribasic (0.825 g, 3.89 mmol), and XPhos Pd G3 (0.2 g, 0.236 mmol, 0.122 equiv.) were suspended in dimethoxyethane (27.8 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred at 120 °C overnight. After completion of the reaction, it was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using 0-100% ACN in DCM to afford 532.9 mg (49% yield) of tert-butyl 4-{5-[4-(tert-butylamino)-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate as a yellow solid. LCMS: [C 28 H 33 N9O2S], desired mass 559.3, measured mass = 560.2 [M+H + ]. 1 H NMR(300MHz,DMSO-d6)δ8.84(d,J=2.4Hz,2H),8.76(d,J=2.3Hz,1H),8.56(s,1H),8.49(s,1H) ,7.85(d,J=4.8Hz,1H),7.12(d,J=4.9Hz,1H),3.53(d,J=6.5Hz,8H),1.55(s,9H),1.43(s,9H).

[0359] Step 3: To a solution of tert-butyl 4-{5-[4-(tert-butylamino)-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl]-1,3,4-thiadiazol-2-yl}piperazine-1-carboxylate (483 mg, 0.86 mmol) in anhydrous dichloromethane (8.6 mL, 0.1 M) was added trifluoroacetic acid (1.3 mL, 17.25 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness. The residue was triturated with diethyl ether. The product was collected by filtration to give 600 mg (100% yield) of 7-[4-tert-butylamino)-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (bis-TFA salt) as a yellow solid. LCMS: [C 23 H 25 N9S], desired mass=459.2, measured mass=460.0[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.34(s,1H),9.04(s,2H),8.92(d,J=2.2Hz,1H),8.83(d,J=2.2Hz,1H),8.56(s,1H) ),8.51(s,1H),7.93(d,J=4.9Hz,1H),7.18(d,J=4.9Hz,1H),3.83-3.75(m,4H),3.31(s,4H),1.57(s,9H).

[0360] Intermediate AS: tert-butyl 8-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate.

[0361] [ka]

[0362] Step 1: To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.5 g, 2.36 mmol) and 2-bromo-1,3,4-thiadiazole (0.972 g, 5.89 mmol) in n-butanol (4.71 mL, 0.5 M) was added N,N-diisopropylethylamine (1.611 mL, 9.42 mmol). The reaction mixture was stirred at 120 °C overnight. After the reaction was complete, it was cooled to room temperature. The volatiles were removed in vacuo, and the residue was transferred to a separatory funnel with a mixture of EtOAc (20 mL) and HO (40 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-50% MeCN in DCM to afford 271 mg (39% yield) of tert-butyl 8-(1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a red oil. LCMS: C 13 H 20 N4O2S theoretical value 296.1, actual value m / z = 296.9 [M+H] + . 1 H NMR(300MHz,chloroform-d)δ8.53(s,1H),4.29(d,J=25.9Hz,2H),3.85(dd,J=48.5,13.1Hz,2H),3 .31(dd,J=38.2,13.1Hz,2H),2.11(dt,J=6.7,3.8Hz,2H),1.90(d,J=17.8Hz,2H),1.43(s,9H).

[0363] Step 2: A suspension of 7-{5-bromo-4-[(oxan-4-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.148 g, 0.37 mmol), tert-butyl 8-(1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.1 g, 0.34 mmol), copper(I) iodide (0.013 g, 0.067 mmol), Xantphos (0.039 g, 0.067 mmol) and cesium carbonate (0.44 g, 1.35 mmol) in anhydrous dioxane (11.25 mL, 0.03 M) was degassed with argon for 15 min and palladium(II) acetate (8 mg, 0.034 mmol) was added. The pressure vessel was sealed and heated at 105 °C overnight. After completion of the reaction, the volatiles were evaporated in vacuo. The residue was purified by silica gel flash chromatography eluting with 0-100% MeCN in DCM followed by 0-10% IPA in DCM to give semi-pure product, which was further triturated with diethyl ether (4 × 10 mL) to give 80 mg (34% yield) of tert-butyl 8-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a bright yellow powder. LCMS: C 31 H 35 N9O3S theoretical value 613.2, actual value m / z = 614.1 [M+H] + . 1 H NMR (300 MHz, DMSO -d6)δ8.85(d,J=2.3Hz,1H),8.78(d,J=2.3Hz,1H),8.67(d,J=7.0Hz,1H),8.52(s,1H),8.31(s,1H),7.85(d,J=4.8Hz,1H),7.13(d,J=4.8H) z,1H),4.35(s,2H),4.01-3.81(m,5H),3.61(s,3H),2.14(s,2H),2.03(s,2H),1.75(d,J=7.4Hz,3H),1.58(d,J=10.8Hz,3H),1.42(s,9H).

[0364] Step 3: To a solution of tert-butyl 8-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.08 g, 0.12 mmol) in anhydrous dichloromethane (11.5 mL, 0.01 M) was added trifluoroacetic acid (0.785 g, 6.88 mmol). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the volatiles were evaporated in vacuo and the residue was triturated with diethyl ether (4 x 10 mL). The residue was dried thoroughly to give 47 mg (77% yield) of 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-8-yl}-1,3,4-thiadiazol-2-yl)-4-[(oxan-4-yl)amino]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS: C 26 H 27 N9OS theoretical value 513.2, actual value m / z = 514.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.13(s,2H),8.92(d,J=2.2Hz,1H),8.83(d,J=2.2Hz,1H),8.59(s,1H),8.24(s,1H),7.94(d,J=4.9Hz,1H),7.18(d,J=4.9H) z,1H),4.50(s,3H),3.94(d,J=11.7Hz,4H),3.39(q,J=6.9Hz,4H),3.25( d,J=12.5Hz,3H),2.55(s,2H),2.18-2.05(m,4H),1.59(d,J=10.5Hz,3H).

[0365] Intermediate AT: 7-[5-(5-{3,9-diazabicyclo[3.3.1]nonan-3-yl}-1,3,4-thiadiazol-2-yl)-4-[(oxan-4-yl)amino]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0366] [ka]

[0367] Step 1: To a solution of tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.55 g, 2.41 mmol) in n-butanol (4.82 mL, 0.5 M) was added 2-bromo-1,3,4-thiadiazole (1.00 g, 6.08 mmol) and DIPEA (1.66 mL, 9.72 mmol). The reaction mixture was stirred at 120 °C for 2 h. The volatiles were removed in vacuo, and the residue was transferred to a separatory funnel using a mixture of EtOAc (50 mL) and HO (100 mL) and then extracted with EtOAc (5 × 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 0–70% MeCN in DCM to give 0.506 g (67% yield) of tert-butyl 3-(1,3,4-thiadiazole). -thiadiazol-2-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate was obtained as a red oil. LCMS: C 13 H 20 N4O3S theoretical value 310.2, actual value m / z = 311.3 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.80(s,1H),4.18(d,J=12.3Hz,2H),3.81(dd,J=12.2,4.4Hz,2H),3.3 8(d,J=4.3Hz,2H),1.92(dt,J=11.8,5.7Hz,1H),1.84-1.61(m,4H),1.51(s,1H),1.44(m,9H).

[0368] Step 2: 7-{5-bromo-4-[(oxan-4-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.208 g, 0.522 mmol), tert-butyl 3-(1,3,4-thiadiazol-2-yl)-3,9-diazabicyclo[3.3.1] in anhydrous dioxane (15.83 mL, 0.03 M) A suspension of nonane-9-carboxylate (0.152 g, 0.475 mmol), CuI (0.018 g, 0.095 mmol), Xantphos (0.055 g, 0.095 mmol), and CsCO (0.619 g, 1.9 mmol) was degassed with argon for 15 min, and Pd(OAc) (0.011 g, 0.047 mmol, 0.1 equiv.) was added. The reaction mixture was stirred at 130 °C in a MW reactor for 2 h. The reaction was incomplete, so additional Xantphos (0.055 g, 0.095 mmol), CsCO (0.619 g, 1.9 mmol), CuI (0.018 g, 0.095 mmol), and Pd(OAc) (0.011 g, 0.047 mmol) were added, and the reaction mixture was degassed by vacuum / argon cycles. The reaction was heated at 130 °C under MW irradiation for an additional 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and the volatiles were evaporated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-100% ACN in DCM followed by 0-10% IPA in DCM to afford 0.056 g (19% yield) of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate as a yellow solid. LCMS: C 32 H 37 N9O3S theoretical value 627.3, actual value m / z = 628.2 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.3Hz,1H),8.77(d,J=2.3Hz,1H),8.71(d,J=7.1Hz, 1H),8.52(s,1H),8.29(s,1H),7.85(d,J=4.8Hz,1H),7.13(d,J=4.8Hz,1H),4.23(d,J=1 2.6Hz,2H),3.98-3.81(m,5H),3.61(t,J=10.7Hz,2H),3.48(d,J=10.5Hz,2H),2.12(d,J =13.4Hz,2H),1.97(s,1H),1.76(d,J=25.0Hz,4H),1.58(d,J=11.3Hz,3H),1.45(s,9H).

[0369] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.056 g, 0.09 mmol) in DCM (0.9 mL, 0.1 M) was added dropwise a solution of 4 M HCl in dioxane (0.707 mL, 2.83 mmol). The reaction mixture was stirred overnight at room temperature. After completion, the solid residue from the reaction mixture was filtered off and washed with DCM. The solid was collected and dried under vacuum to give 0.038 g (75% yield) of 7-[5-(5-{3,9-diazabicyclo[3.3.1]nonan-3-yl}-1,3,4-thiadiazol-2-yl)-4-[(oxan-4-yl)amino]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (2×HCl salt) as a yellow solid. LCMS: C 27 H 29 N9OS theoretical value 527.2, actual value m / z = 528.2 [M+H] + , 1 H NMR (300MHz, DMSO-d). d6)δ9.68-9.32(m,3H),8.98(d,J=2.3Hz,1H ),8.87(d,J=2.2Hz,1H),8.57(s,1H),8.16(s,1H),8.10(s,1H),7.23(d,J=5.0Hz,1H),4.11(d,J=13.1H) z,3H),3.88(dd,J=33.2,15.8Hz,6H),3.61(t,J=10.8Hz,3H),2.17-1.94(m,6H),1.62(d,J=11.5Hz,4H).

[0370] Intermediate AU: 7-(4-{[(1R-1-cyanoethyl]amino}-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0371] [ka]

[0372] Step 1: tert-Butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 0.94 mmol, 1.0 equiv.) was dissolved in anhydrous dimethyl sulfoxide (9.39 mL, 0.1 M). To this was added D-alaninamide hydrochloride (1.169 g, 9.4 mmol, 10.0 equiv.) and sodium bicarbonate (1.183 g, 14.08 mmol, 15.0 equiv.). The resulting mixture was stirred at 120 °C for 1 hour. After the reaction was complete, it was cooled to room temperature, directly injected onto a column, and purified using 0-60% water in ACN as the mobile phase to give 0.3 g (53% yield) of tert-butyl 3-[5-(4-{[(1R-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS: [C 29 H 32 N 10O3S], desired mass=600.7, measured mass=601.2[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.90-8.81(m,2H),8.64(d,J=2.3Hz,1H),8.51(s,1H),8.12(s,1H),7.83(d,J=4.8Hz,1H),7.79(s,1H),7.23(s,1H),7.1 3(d,J=4.8Hz,1H),4.38-4.19(m,3H),3.79-3.63(m,2H),3.44-3.35(m, 2H), 1.93 (s, 2H), 1.86-1.69 (m, 3H), 1.50 (d, J=6.8Hz, 3H), 1.45 (s, 9H).

[0373] Step 2: tert-Butyl 3-[5-(4-{[(1R-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3- [(1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate] (0.3 g, 0.499 mmol, 1.0 equiv.) was suspended in anhydrous dichloromethane (9.99 mL, 0.05 M), followed by the addition of anhydrous pyridine (0.322 mL, 3.995 mmol, 8.0 equiv.). Trifluoroacetic anhydride (0.315 g, 1.498 mmol, 3.0 equiv.) was added to the resulting suspension, and the reaction mixture was stirred at room temperature for 30 minutes. The formation of a clear solution was observed. The reaction mixture was then concentrated in vacuo, dissolved in a minimum amount of DCM, and loaded onto a column. The crude material was purified by flash chromatography using DCM-IPA 0-10% as the mobile phase to give 0.182 g (62% yield) of tert-butyl 3-[5-(4-{[(1R-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS: [C 29 H 30 N 10 O2S], desired mass=582.6, measured mass=583.8[M+H] + .1 H NMR(300MHz,DMSO-d6)δ8.87(d,J=2.3Hz,1H),8.84(d,J=6.9Hz,1H),8.68(d,J=2.3Hz,1H),8.63(s,1H),8.36(s,1H),7.88(d,J=4.8Hz,1H),7.15 (d,J=4.8Hz,1H),5.11-4.97(m,1H),4.40-4.22(m,2H),3.76-3.64(m,2H ),3.42-3.37(m,2H),2.04-1.86(m,2H),1.84-1.69(m,5H),1.44(s,9H).

[0374] Step 3: tert-Butyl 3-[5-(4-{[(1R)-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.182 g, 0.312 mmol, 1.0 equiv) was dissolved in anhydrous DCM (6.25 mL, 0.05 M). To this was added TFA (0.712 g, 6.247 mmol, 20.0 equiv). The resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, it was concentrated in vacuo. The residue was triturated and sonicated with diethyl ether to give a yellow precipitate which was collected by filtration and dried in vacuo overnight to give 0.288 g (92% yield) of 7-(4-{[(1R-1-cyanoethyl]amino}-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS: [C 28 H 24 F6N 10 04S], desired mass = 482.5, measured mass = 483.8 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ9.13(s,1H),9.05(s,1H),8.89(d,J=2.2Hz,1H),8.84 (d,J=6.9Hz,1H),8.70(d,J=2.3Hz,1H),8.67(s,1H),8.37(s,1H),7.90(d,J= 4.8Hz,1H),7.17(d,J=4.8Hz,1H),5.08(p,J=6.8Hz,1H),4.28-4.19(m,2H),3 .92-3.83(m,2H),3.64-3.58(m,2H),2.12-1.93(m,4H),1.78(d,J=6.9Hz,3H).

[0375] Intermediate AV: 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isoxazol-4-ylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0376] [ka]

[0377] Step 1: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.94 mmol) in AcOH (9.5 mL, 0.1 M) was added 1,2-oxazol-4-amine (789 mg, 9.4 mmol). The reaction mixture was stirred overnight at room temperature. After completion of the reaction, acetic acid was evaporated and the residue was partitioned between saturated NaHCO3 (50 mL) and DCM (100 mL). The layers were separated, and the aqueous layer was further washed with DCM (2 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL). The DCM layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 900 mg of crude material. The crude material was combined with the trial reaction and purified by silica gel flash chromatography using 0-10% IPA in DCM to give 600 mg of semi-pure product. The RPFC was then repurified using ACN / water containing 0.1% FA, and then flushed from the column using 95% THF, 0.1% TFA, and 4.9% water to give 305 mg (54% yield) of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isoxazol-4-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. LCMS: [C29H28N10O3S], desired mass = 596.2, measured mass = 597.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.12(s,1H),9.28(s,1H),9.02(s,1H),8.70-8.63(m,2H),8.41(s,1H),8.19(d,J=5.8Hz,1H),7.87(d,J=4.8Hz,1H), 7.13(d,J=4.9Hz,1H),4.31(s,2H),3.71(d,J=11.6Hz,2H),3.41(d,J=11.1Hz,2H),1.89(d,J=24.9Hz,2H),1.77(d,J=7.5Hz,2H),1.45(s,9H).

[0378] Step 2: To a solution of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isoxazol-4-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (305 mg, 0.511 mmol) in anhydrous DCM (3.8 mL, 0.2 M) was added TFA (1.72 g, 15.11 mmol) and the resulting mixture was kept at room temperature for 1 hour. The volatiles were removed by evaporation. The crude material was triturated with EtO (4 × 10 mL) to give 315 mg (100% yield) of 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isoxazol-4-ylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a pale yellow solid. LCMS: [C24H20N10OS], desired mass = 496.15, observed mass = 497.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.12(s,1H),9.29(s,3H),9.01(s,1H),8.85(d,J=2.2H z,1H),8.69(d,J=1.6Hz,2H),8.38(s,1H),7.87(d,J=4.9Hz,1H),7.13(d,J=4.8Hz, 1H),4.24(s,2H),3.88(d,J=12.7Hz,2H),3.63(d,J=12.8Hz,2H),2.09-1.92(m,4H).

[0379] Intermediate AW: 7-(4-{[(1S)-1-cyanoethyl]amino}-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0380] [ka]

[0381] Step 1: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.471 mg, 0.88 mmol) in N-methyl-pyrrolidone (5.9 mL, 0.15 M), L-alaninamide hydrochloride (0.33 g, 2.65 mmol) and N,N-diisopropylethylamine (0.79 mL, 4.42 mmol) were added at room temperature. The reaction mixture was stirred at 120 °C overnight. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-6% MeOH in DCM to give 0.332 g (62% yield) of tert-butyl 3-[5-(4-{[(1S-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow gum. LCMS: [C 29 H 32 N 10 O3S], desired mass=600.2, measured mass=601.3[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.85(q,J=2.3,1.6Hz,2H),8.63(d,J=2.2Hz,1H),8.5 1(s,1H),8.11(s,1H),7.82(d,J=4.8Hz,1H),7.76(s,1H),7.22(s,1H),7.12(d ,J=4.8Hz,1H),4.27(d,J=7.1Hz,3H),3.70(d,J=11.8Hz,2H),3.37(d,J=11.8H z,3H),1.91(s,2H),1.76(d,J=7.4Hz,2H),1.50(d,J=6.7Hz,3H),1.44(s,9H).

[0382] Step 2: To an ice-cold solution of tert-butyl 3-[5-(4-{[(1S)-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (332 mg, 0.55 mmol) in anhydrous dichloromethane (42.5 mL, 0.01 M), trifluoroacetic anhydride (0.23 mL, 1.66 mmol) and pyridine anhydride (0.36 mL, 4.42 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-5% MeOH in DCM to give 0.195 g (63% yield) of tert-butyl 3-[5-(4-{[(1S-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl ]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a yellow solid. LCMS: [C 29 H 30 N 10 O2S], desired mass = 582.2, measured mass = 583.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.91-8.79(m,2H),8.68(d,J=2.3Hz,1H),8.63(s,1H),8.37(s,1H),7.88(d,J=4.8Hz,1H),7.15(d,J=4.9Hz,1H), 5.04(t,J=6.8Hz,1H),4.29(s,2H),3.70(d,J=11.8Hz,2H),3.39(d,J=11.7Hz,2H),1.98-1.89(m,2H),1.77(t,J=6.7Hz,5H),1.45(s,9H).

[0383] Step 3: To a solution of tert-butyl 3-[5-(4-{[(1S-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.195 g, 0.35 mmol) in anhydrous dichloromethane (1.75 mL, 0.2 M) was added trifluoroacetic acid (0.54 mL, 7.00 mmol) at room temperature. The reaction mixture was stirred at room temperature. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by trituration with diethyl ether (3 x 20 mL) to give 227.8 mg (96% yield) of 7-(4-{[(1S)-1-cyanoethyl]amino}-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS: [C 24 H 22 N 10 S], desired mass=482.2, measured mass=483.0[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.19-9.07(m,1H),9.10-8.98(m,1H),8.89(d,J=2.3Hz,1 H),8.86(d,J=8.1Hz,1H),8.70(d,J=2.3Hz,1H),8.67(s,1H),8.35(s,1H),7.90(d ,J=4.7Hz,1H),7.16(d,J=4.9Hz,1H),5.08(t,J=6.9Hz,1H),4.22(s,2H),3.87(d ,J=13.1Hz,2H),3.60(d,J=12.7Hz,2H),2.04-1.92(m,4H),1.77(d,J=6.9Hz,3H).

[0384] Intermediate AX: 7-{4-[(1-cyano-1-methylethyl)amino]-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0385] [ka]

[0386] Step 1: tert-Butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 0.939 mmol, 1.0 equiv) was dissolved in anhydrous dimethyl sulfoxide (9.39 mL, 0.1 M), followed by the addition of 2-amino-2-methylpropanamide hydrochloride (1.301 g, 9.388 mmol, 10.0 equiv) and sodium bicarbonate (1.183 g, 14.082 mmol, 15.0 equiv), and the resulting mixture was stirred at 120° C. overnight. The DMSO was removed in vacuo and the residue was mixed with water. The precipitate that formed was collected by filtration and dried in vacuo to give 0.6 g (59% yield) of crude tert-butyl 3-(5-{4-[(1-carbamoyl-1-methylethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS: [C 30 H 34 N 10 O3S], desired mass=614.7, measured mass=615.8[M+H] + .

[0387] Step 2: Crude tert-butyl 3-(5-{4-[(1-carbamoyl-1-methylethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.6 g, 0.56 mmol, 1.0 equiv.) was suspended in anhydrous dichloromethane (11.13 mL, 0.05 M), followed by the addition of anhydrous pyridine (0.359 mL, 4.451 mmol, 8.0 equiv.). Trifluoroacetic anhydride (0.351 g, 1.67 mmol, 3.0 equiv.) was added to the resulting suspension, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo, dissolved in a minimum amount of DCM, and purified twice by FC using DCM-IPA 0-7% as the mobile phase followed by DCM-ACN 0-30% as the mobile phase to give 0.31 g (93% yield) of tert-butyl 3-(5-{4-[(1-cyano-1-methylethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS: [C 30 H 32 N 10 O2S], desired mass=596.7, measured mass=597.9[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.88(d,J=2.2Hz,1H),8.71(d,J=2.2Hz,1H),8.69(s,1H),8.65(s,1H),7.90(d,J=4.8Hz,1H), 7.16(d,J=4.8Hz,1H),4.29(s,2H),3.71(d,J=11.9Hz,2H),3.39(d,J=11.3Hz,2H),1.92(s,6H),1.75(d,J=7.4Hz,4H),1.45(s,9H).

[0388] Step 3: tert-Butyl 3-(5-{4-[(1-cyano-1-methylethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.31 g, 0.52 mmol, 1.0 equiv.) was dissolved in anhydrous DCM (5.2 mL, 0.1 M) followed by TFA (1.185 g, 10.39 mmol, 20.0 equiv.). The resulting mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was triturated and sonicated with diethyl ether to give a yellow precipitate, which was collected by filtration and dried in vacuo overnight to give 0.255 g (76% yield) of 7-{4-[(1-cyano-1-methylethyl)amino]-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazol-2-yl)pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS: [C 25 H 24 N 10 S], desired mass=496.6, measured mass=497.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.27-9.09(m,2H),9.08(s,1H),8.90(d,J=2.2Hz,1H),8.73(d,J=2.2Hz,1H),8.70(s,1H),8.69(s,1H),7.9 1(d,J=4.8Hz,1H),7.17(d,J=4.8Hz,1H),4.25-4.18(m,2H),3.93-3.80(m,2H),3.67-3.57(m,2H),2.07-1.95(m,4H),1.93(s,6H).

[0389] Intermediate AY: 7-[5-(5-{3-oxa-7,9-diazabicyclo[3.3.1] {nonan-7-yl}-1,3,4-thiadiazol-2-yl)-4-[(oxan-4-yl)amino]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile; 2× trifluoroacetate salt

[0390] [ka]

[0391] Step 1: To a solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.55 g, 2.41 mmol) in n-butanol (4.82 mL, 0.5 M) was added 2-bromo-1,3,4-thiadiazole (0.99 g, 6.02 mmol) and DIPEA (1.65 mL, 9.64 mmol). The reaction mixture was stirred at 120 °C for 1 h. The volatiles were removed in vacuo, and the residue was transferred to a separatory funnel using a mixture of EtOAc (50 mL) and HO (100 mL), followed by extraction with EtOAc (5 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography using 0-80% ACN in DCM to give 0.467 g (62% yield) of tert-butyl 7-(1,3,4-thiadiazol-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate as a red solid. LCMS: C 13 H 20 N4O3S theoretical value 312.4, actual value m / z = 313.0 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.75(s,1H),4.01(d,J=9.6Hz,2H),3.97-3.84(m,4H),3.62(dt,J=11.5,2.5Hz,2H),3.44(d,J=12.9Hz,2H),1.44(s,9H).

[0392] Step 2: To a suspension of 7-{5-bromo-4-[(oxan-4-yl)amino]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.42 g, 1.06 mmol) in dioxane (32.0 mL, 0.03 M) was added tert-butyl 7-(1,3,4-thiadiazol-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.312 g, 0.959 mmol), CuI (0.037 g, 0.19 mmol), Xantphos (0.111 g, 0.19 mmol), and CsCO (1.25 g, 3.84 mmol). The reaction mixture was degassed with argon for 15 minutes, and then Pd(OAc) (0.022 g, 0.096 mmol) was added. The reaction mixture was stirred at 130 °C for 2 hours using microwave heating. It was then cooled to room temperature, and additional Xantphos (0.111 g, 0.19 mmol), CsCO (1.25 g, 3.84 mmol), CuI (0.037 g, 0.19 mmol), and Pd(OAc) (0.022 g, 0.096 mmol) were added. The mixture was stirred at 130 °C for an additional 2 hours using microwave heating. Volatiles were evaporated in vacuo. The residue was purified by silica gel flash chromatography, eluting with 0–100% MeCN in DCM. The resulting semi-pure product was re-purified using reverse-phase flash chromatography eluting with MeCN in water (5-75% MeCN) to give 0.09 g (15% yield) of tert-butyl 7-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazine]]propanol. {4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate was obtained as a yellow solid. LCMS: C 31 H 35 N9O4S theoretical value 629.7, actual value m / z = 630.2 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.3Hz,1H),8.77(d,J=2.3Hz,1H),8.70(s,1H),8.51(s,1H),8.29(s,1H),7.84(d,J=4.8Hz, 1H),7.13(d,J=4.8Hz,1H),4.13-3.75(m,11H),3.60(dt,J=20.0,10.5Hz,8H),2.12(d,J=15.5Hz,3H),1.58(d,J=10.0Hz,3H).

[0393] Step 3: To a solution of tert-butyl 7-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazol-2-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.09 g, 0.143 mmol) in DCM (14.3 mL, 0.01 M) was added trifluoroacetic acid (0.978 g, 8.58 mmol). The reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. The resulting crude material was triturated with EtO (4 x 20 mL) and dried to give 0.08 g (83% yield) of 7-[5-(5-{3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl}-1,3,4-thiadiazol-2-yl)-4-[(oxan-4-yl)amino]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile; 2x trifluoroacetate salt as a yellow solid. LCMS: C 26 H 27 N9O2S theoretical value 529.2, actual value m / z = 530.3 [M+H] + , Method: LCMS2-036-5-80-80-7-1-25-UV-Rot, RT=2.81 min, Purity: 95.71% (254 nm). 1H NMR(300MHz,DMSO-d6)δ8.99(d,J=2.2Hz,1H),8.87(d,J=2.2Hz,1H),8.62(s,1H),8.14-8.04(m,2H),7.25(d,J=5.0Hz,1H),4.32(d,J=13 .9Hz,2H),4.12(d,J=12.5Hz,3H),4.03-3.83(m,6H),3.67-3.54(m,2H),2.57(d,J=5.5Hz,4H),2.10(t,J=6.8Hz,2H),1.72-1.57(m,2H).

[0394] B. Synthesis of LHM building blocks HA-1: 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehyde

[0395] [ka]

[0396] Step 1: Under an inert atmosphere of nitrogen, a 5 L four-necked round-bottom flask was charged with 2,6-dichloropyridine (150.00 g, 1013.58 mmol, 1.00 equiv), dimethylformamide (3 L), and NaH (272.00 g, 11334 mmol, 11.18 equiv, 65%). This was followed by the dropwise addition of BnOH (329.50 g, 3050 mmol, 3.01 equiv) with stirring at 0° C. The resulting solution was stirred at 80° C. for 4 hours. The reaction mixture was cooled. The reaction was then quenched by adding 7 L of water / ice. The solid was collected by filtration and concentrated. This afforded 276 g (93.46%) of 2,6-bis(benzyloxy)pyridine as a gray solid. LCMS: (ES, m / z): [M+1] + =292;T=1.48 minutes.

[0397] Step 2: Under an inert atmosphere of nitrogen gas, a 3 L four-necked round-bottom flask was charged with 2,6-bis(benzyloxy)pyridine (276.00 g, 947.3 mmol, 1.00 equiv.), CHCN (2.76 L), and KCO (445.00 g, 3196.54 mmol, 3.37 equiv.). This was followed by the dropwise addition of Br (151.70 g, 949.26 mmol, 1.00 equiv.) at 0 °C. The resulting solution was stirred at room temperature for 4 hours. The resulting reaction mixture was concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (10%). This afforded 253 g (72.13%) of 2,6-bis(benzyloxy)-3-bromopyridine as a white solid. LCMS: [M+1] + =370.

[0398] Step 3: A 3 L four-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-bis(benzyloxy)-3-bromopyridine (253.00 g, 683.32 mmol, 1.00 equiv.), dioxane (2.53 L), bis(pinacolato)diboron (261.00 g, 1027.80 mmol, 1.50 equiv.), potassium acetate (134.00 g, 1365.36 mmol, 2.00 equiv.), and Pd(dppf)Cl (25.10 g, 34.29 mmol, 0.05 equiv.). The resulting solution was stirred at 100 °C overnight. The reaction mixture was cooled. The resulting mixture was concentrated and loaded onto a silica gel column using ethyl acetate / petroleum ether (15%). This gave 200 g (70.14%) of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a white solid.

[0399] Step 4: A 3 L four-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2-fluoro-5-iodopyridine (200.00 g, 896.90 mmol, 1.00 equiv), DMSO (2.00 L), piperidin-4-ylmethanol (128.90 g, 1119.15 mmol, 1.25 equiv), and DIEA (347.00 g, 2684.86 mmol, 3.00 equiv). The resulting solution was stirred at 90° C. for 3 days. The reaction mixture was cooled. 2×2 L of EA was added to the resulting mixture, and the organic layers were combined. The resulting mixture was washed with 3×2 L of brine. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (35%). This gave 182 g (63.78%) of [1-(5-iodopyridin-2-yl)piperidin-4-yl]methanol as a yellow oil. LCMS: [M+1] + =319.

[0400] Step 5: To a 3 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, add [1-(5-iodopyridin-2-yl)piperidin-4-yl]methanol (182.00 g, 572.04 mmol, 1.00 equiv.), tetrahydrofuran (1.82 L), water (364.00 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (298.40 g, 715.05 mmol, 1.25 equiv.), KCO (157.90 g, 1134.23 mmol, 1.98 equiv.), tetrakis(triphenylphosphine)palladium(0) (66. 00g (57.11mmol, 0.10eq). The resulting solution was stirred at 90°C overnight. The reaction mixture was cooled. The resulting mixture was extracted with 2x3L of EA, and the organic layer was washed with 3x3L of brine. The combined organic layers were concentrated. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (85%). This afforded 140g (50.82%) of [1-[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl]piperidin-4-yl]methanol as a green solid. LCMS: [M+1] + =482;.

[0401] Step 6: A 2 L round-bottom flask was charged with [1-[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl]piperidin-4-yl]methanol (35.00 g, 72.67 mmol, 1.00 equiv.), tetrahydrofuran (120 mL), and Pd / C (10.00 g, 10%). The resulting solution was stirred overnight under a hydrogen atmosphere (4 atm). The Pd / C was then filtered, followed by the addition of another 10 g of Pd / C (10%), and then stirred again overnight. The filtration / addition procedure was repeated three times. The solid was filtered. The resulting filtrate was concentrated and washed with 3 x 100 mL of EA. This gave 64 g of crude product. 8 g of the crude product was used directly in the next step, and the remaining 56 g of the crude product was further purified by flash chromatography. This gave 45 g of 6'-[4-(hydroxymethyl)piperidin-1-yl]-1,3-dihydro-[3,3'-bipyridine]-2,6-dione as a yellow solid.

[0402] LCMS:[M+1] + =304. 1 H-NMR:(300MHZ,DMSO-d6,ppm):δ10.79(s,1H),7.93(d,J=2.3Hz,1H),7.35(dd,J=8.8,2.5Hz,1 H),6.79(d,J=8.8Hz,1H),4.45(t,J=5.1Hz,1H),4.27(d,J=12.9Hz,2H),3.72(dd,J=12.0,4.9Hz ,1H),3.27(t,J=5.1Hz,2H),2.82-2.59(m,3H),2.58-2.43(m,1H),2.17(qd,J=12.5,4.4Hz,1H), 1.98(dq,J=8.5,4.7Hz,1H),1.71(d,J=13.3Hz,2H),1.60(br,1H),1.11(qd,J=11.9,3.8Hz,2H).

[0403] Step 7: Under a nitrogen atmosphere, a 1 L three-necked round-bottom flask was charged with 3-[6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl]piperidine-2,6-dione (8.00 g, 26.37 mmol, 1.00 equiv.) and DCM (400.00 mL). This was followed by the addition of Dess-Martin periodinane (12.30 g, 31.59 mmol, 1.20 equiv.) at 0° C. The resulting solution was stirred at 0° C. for 2 hours. The reaction mixture was filtered, and the filtrate was washed with brine (200 mL), dried over Na2SO4, concentrated in vacuo, and purified on a silica gel column using DCM / EA (3:2). The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (15%). This gave 5 g (62.92%) of 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carbaldehyde (HA-1) as a grey solid. LCMS: (ES, m / z): [M+1] + =302. 1 H-NMR:(300MHZ,DMSO-d6,ppm):δ10.80(s,1H),9.62(s,1H),7.95(d,J=2.5Hz,1H),7.3 9(dd,J=8.9,2.5Hz,1H),6.83(d,J=8.8Hz,1H),4.12(dd,J=13.1,4.2Hz,2H),3.73(dd, J=12.0,4.9Hz,1H),3.10-2.95(m,2H),2.64(tdd,J=24.6,11.1,4.8Hz,2H),2.18(qd,J =12.4,4.4Hz,1H),2.03-1.93(m,1H),1.89(dd,J=13.2,3.6Hz,3H),1.57-1.39(m,2H).

[0404] HA-2: rac-(R)-3-(6-(piperidin-4-yl)pyridin-3-yl ) Piperidine-2,6-dione

[0405] [ka]

[0406] Step 1: To a mixture of 2,5-dibromopyridine (10 g, 42.21 mmol, 1 equiv.) in 1,4-dioxane (100 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (14.36 g, 46.43 mmol, 1.10 equiv.), NaCO (6.71 g, 63.32 mmol, 1.5 equiv.), and Pd(PPh) (1.46 g, 1.27 mmol, 0.03 equiv.) in HO (10 mL) were added. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give tert-butyl 5-bromo-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carboxylate (10 g, 69.83%) as a yellow solid. LCMS (ESI) (C 15 H 21 BrN2O2)[M+1] + Calculated value: 339.1; Measured value: 339.1.

[0407] Step 2: To a mixture of tert-butyl 4-(5-bromopyridin-2-yl)piperidine-1-carboxylate (1 g, 2.93 mmol, 1 equivalent) in THF (9 mL), 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (1.18 g, 3.52 mmol, 1.2 equivalents) and KCO (0.81 g, 5.86 mmol, 2 equivalents) and Pd(PPh) (0.34 g, 0.29 mmol, 0.1 equivalents) were added in HO (3 mL). The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1) to give tert-butyl 5-[2,6-bis(benzyloxy)pyridin-3-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carboxylate (1.3 g, 80.71%) as a white solid. LCMS (ESI) (C 34 H 35 N3O4)[M+1] +Calculated value: 550.3; Measured value: 550.3.

[0408] Step 3: To a mixture of tert-butyl 5-[2,6-bis(benzyloxy)pyridin-3-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carboxylate (1.3 g, 2.37 mmol, 1 equivalent) in THF (15 mL) was added Pd / C (1 g). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered and then concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using CH3CN / HO (1 / 1) to give tert-butyl 4-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-1- The carboxylate (0.35 g, 39.63%) was obtained as a brown solid. LCMS (ESI) (C 20 H 27 N3O4)[M+1] + Calculated value: 374.2; Measured value: 374.0.

[0409] Step 4: A mixture of tert-butyl 4-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-1-carboxylate (350 mg, 0.94 mmol, 1 equiv.) in HCl / dioxane (15 mL, 4 M) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. This afforded rac-(3R)-3-[6-(piperidin-4-yl)pyridin-3-yl]piperidine-2,6-dione hydrochloride (HA-2) (290 mg, 99.88%) as a pink solid. LCMS (ESI) (C 15 H 19 N3O2)[M+1] + Calculated value: 274.2; Measured value: 274.1. 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.19(s,1H),9.09(s,1H),8.68-8.63(m,1 H),8.22-8.15(m,1H),7.73-7.66(m,1H),4.20-4.12(m,1H),3.44-3.36(m,2H), 3.32(s,1H),3.09-3.02(m,1H),3.02-2.96(m,1H),2.80-2.67(m,1H),2.64-2.5 5(m,1H),2.43-2.27(m,1H),2.18-2.11(m,2H),2.06(s,2H),2.11-1.96(m,1H).

[0410] HA-3: 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-4-carbaldehyde

[0411] [ka]

[0412] Step 1: To a solution of 2-fluoro-4-bromo-iodobenzene (42.1 g, 365 mmol, 1.10 equiv) and piperidin-4-ylmethanol (100 g, 332 mmol, 1.00 equiv) in DMSO (1000 mL) under N was added L-proline (17.4 g, 132 mmol, 0.400 equiv), KCO (91.8 g, 664 mmol, 2.00 equiv), and CuI (12.6 g, 66.4 mmol, 0.200 equiv). The reaction was stirred at 90 °C for 12 h. The reaction mixture was cooled to 20 °C and poured into saturated NH Cl solution (1000 mL). The product was extracted with ethyl acetate (1000 mL). * The combined organic layer was washed with brine (1000 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1, R f =0.55) to give the desired product (10.7 g, 35.6 mmol, 10.7% yield) as a yellow solid. LCMS: m / z=290.0 (M+H) + .

[0413] Step 2: (1-(4-bromo-2-fluorophenyl)piperidin-4-yl)methanol (11.6 g, 38.6 mmol, 1.00 equiv.), 2,6-bis(benzyloxy)-3-(4,4,5-trimethyl)- ... To a solution of 1,3,2-dioxaborolan-2-yl)pyridine (17.7 g, 42.4 mmol, 1.10 equiv.), K2CO3 (16.0 g, 115 mmol, 3.00 equiv.) under N2, Pd(dppf)Cl2·CHCl2 (3.15 g, 3.86 mmol, 0.100 equiv.) was added. The reaction mixture was then stirred at 110 °C for 12 h. The mixture was cooled to 25 °C. The reaction mixture was then poured into HO (300 mL) and extracted with EtOAc (200 mL). * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated. The crude product was purified by MPLC (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) (petroleum ether / ethyl acetate = 1 / 1, R f =0.5) to give compound 11 (10.7 g, 20.5 mmol, 53.2% yield) as a pale yellow solid. LCMS: m / z=499.4 (M+H). + .

[0414] Step 3: To a solution of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)piperidin-4-yl)methanol (11.6 g, 23.2 mmol, 1.00 equiv) in THF (120 mL) and EtOH (120 mL) under N was added AcOH (4.19 g, 69.8 mmol, 3.99 mL, 3.00 equiv), Pd / C (2.90 g, 10% purity), and Pd(OH) (3.01 g, 4.29 mmol, 20% purity). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 psi) at 80 °C for 12 h. The reaction was cooled to 20 °C and filtered. The filtrate was concentrated. The crude product was used in the next step without purification. The desired product (8.40 g, crude) was obtained as a yellow solid. LCMS: m / z=321.2 (M+H) + .

[0415] Step 4: To a solution of 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (8.40 g, 26.2 mmol, 1.00 equiv.) in DMSO (90.0 mL) was added DMP (22.2 g, 52.4 mmol, 16.2 mL, 2.00 equiv.) in portions. The reaction was stirred at 25 °C for 12 h. The pH of the reaction mixture was adjusted to pH = 10 with saturated aqueous Na2CO3, and the aqueous layer was extracted with ethyl acetate (400 mL). * The combined organic layer was extracted with NaSO solution (500 mL * The crude product was triturated with ethyl acetate (100 mL) at 25° C. for 12 hours to give HA-3 (2.50 g, 7.60 mmol, 28.9% yield) as a yellow solid. LCMS: m / z=317.1 (M−H). + . 1 H NMR(400MHz,DMSO-d6)δ10.8(s,1H),9.64(s,1H),7.06-6.90(s,3H),3.83-3.76(m,1H),3.29-3.24(m,2H),2.76( t,J=10.0Hz,2H),2.69-2.60(m,1H),2.48-2.41(m,2H),2.24-2.13(m,1H),2.04-1.91(m,3H),1.71-1.58(m,2H).

[0416] HA-4: 1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidine-4-carbaldehyde

[0417] [ka]

[0418] HA-4 was synthesized according to the same procedure as HA-3, replacing 4-bromo-2-fluoro-1-iodobenzene with 1-bromo-2-fluoro-4-iodobenzene in step 1 to give the title compound. LCMS: m / z=317.1 (M−H). +. 1 H NMR:(400MHz,DMSO-d6)δ10.79(s,1H),9.62(s,1H) ,7.07(t,J=8.8Hz,1H),6.77-6.69(m,2H),3.91-3.84(m,1H),3.67-3.59(m,2H),2.91-2.81(m,2H),2.76-2 .65(m,1H),2.56-2.52(m,1H),2.49-2.45(m,1H),2.20-2.07(m,1H),1.97-1.86(m,3H),1.61-1.49(m,2H).

[0419] HA-5: rac-(R)-3-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione

[0420] [ka]

[0421] Step 1: To a 40 mL vial was added tert-butyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1000.00 mg, 3.20 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1470.31 mg, 3.52 mmol), potassium phosphate tribasic (2.04 g, 9.61 mmol), Pd(dppf)Cl·DCM (0.26 g, 0.32 mmol), dioxane (7.00 mL), and water (2.50 mL). The reaction mixture was stirred for 1 hour at RT. The mixture was degassed with nitrogen for 15 minutes and then stirred at 90°C for 16 hours. The reaction mixture was then diluted with water and EtOAc and then filtered through Celite. The product was extracted with EtOAc (3x), dried over MgSO4, and concentrated. The resulting residue was purified by column chromatography (80g silica, 0-25% EtOAc / hexanes) to give tert-butyl 6-[2,6-bis(benzyloxy)pyridin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate as a colorless oil (1.48g, 88%). LCMS C 33 H34 N2O4 theoretical value: 522.3, measured value: m / z = 523.3 [M+H] + .

[0422] Step 2: To a 40 mL vial was added tert-butyl 6-[2,6-bis(benzyloxy)pyridin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1480.00 mg, 2.83 mmol), Pd / C (700.00 mg), THF (10.00 mL), and EtOH (10.00 mL). The reaction mixture was sparged with hydrogen for 5 minutes, and then the reaction was stirred under a hydrogen atmosphere (balloon) for 16 hours. The reaction mixture was filtered through Celite and then concentrated. The resulting residue was purified by column chromatography (40 g silica, 0-10% MeOH / DCM) to afford rac-tert-butyl 6-[(3R)-2,6-dioxopiperidin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate as a white solid (852 mg, 87%). LCMS C 19 H 24 N2O4 theoretical value: 344.2, measured value: m / z = 345.2 [M+H] + .

[0423] Step 3: To a 40 mL vial was added rac-tert-butyl 6-[(3R)-2,6-dioxopiperidin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (852.00 mg, 2.47 mmol) and DCM (2.00 mL). To the reaction mixture was added dropwise 4M hydrogen chloride in dioxane (6.18 mL, 0.90 g, 24.74 mmol). After 1 h, the reaction mixture was concentrated to give the title compound as a white solid (707 mg, quantitative yield). LCMS C 14 H 16 N2O2 theoretical value: 244.1, measured value: m / z = 245.0 [M+H] + .

[0424] HA-6: 1-{4-[4-({4-[2-(6,6-dimethyl-1,4,5,7-tetrahydroindazol-3-yl)-1H-indole-5-carbonyl]piperazin-1-yl}methyl)piperidin-1-yl]-2-fluorophenyl}-1,3-diazinan-2,4-dione

[0425] [ka]

[0426] Step 1: To a mixture of 4-bromo-2-fluoroaniline (20 g, 105.26 mmol, 1 equiv.) in AcOH (80 mL) and H2SO4 (1 mL) was added acrylic acid (22.75 g, 315.77 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified on a C18 reverse-phase column using ACN / H2O (1 / 4). This afforded 3-[(4-bromo-2-fluorophenyl)amino]propanoic acid (13 g, 42.41%) as an off-white solid. LCMS (ESI) (C9H9BrFNO2) [M+1] + Calculated value: 262.0; Measured value: 262.0.

[0427] Step 2: To a mixture of 3-[(4-bromo-2-fluorophenyl)amino]propanoic acid (13 g, 49.6 mmol, 1 equiv.) in MeOH (30 mL) was added SOCl (54 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. This afforded methyl 3-[(4-bromo-2-fluorophenyl)amino]propanoate (9 g, crude) as a brown oil. LCMS (ESI) (C 10 H 11 BrFNO2)[M+1] + Calculated value: 276.0; Measured value: 276.0.

[0428] Step 3: To a mixture of methyl 3-[(4-bromo-2-fluorophenyl)amino]propanoate (9 g, 32.6 mmol, 1 eq.) in AcOH (40 mL) and DCM (40 mL), potassium cyanate (7.93 g, 97.79 mmol, 3 eq.) was added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column using ACN / H2O (3 / 7). This gave methyl 3-[(4-bromo-2-fluorophenyl)(carbamoyl)amino]propanoate (3.5 g, 30.28%) as a white solid. LCMS (ESI) (C 11 H 12 BrFN2O3)[M+1] + Calculated value: 319.0; Measured value: 319.0.

[0429] Step 4: To a mixture of methyl 3-[(4-bromo-2-fluorophenyl)(carbamoyl)amino]propanoate (3.5 g, 10.97 mmol, 1 equiv.) in THF (20 mL) was added potassium trimethylsilanolate (3.52 g, 27.42 mmol, 2.5 (equivalent) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(4-bromo-2-fluorophenyl)-1,3-diazinan-2,4-dione (2 g, crude) as a white solid. LCMS (ESI) (C 10 H8BrFN2O2)[M+1] + Calculated value: 287.0; Measured value: 287.0.

[0430] Step 5: To a mixture of 1-(4-bromo-2-fluorophenyl)-1,3-diazinan-2,4-dione (2.7 g, 9.41 mmol, 1 equiv.) in dioxane (25 mL), piperidin-4-ylmethanol (2.29 g, 19.85 mmol, 3 equiv.), Pd(OAc) (0.21 g, 0.94 mmol, 0.1 equiv.), CsCO (9.19 g, 28.22 mmol, 3 equiv.), and t-BuXPhos (0.80 g, 1.88 mmol, 0.2 equiv.) were added. The resulting mixture was stirred at 90° C. under a nitrogen atmosphere overnight. The residue was purified by C18 reverse-phase column with ACN / HO (1 / 2) to give 1-{2-fluoro-4-[4-(hydroxymethyl)piperidin-1-yl]phenyl}-1,3-diazinan-2,4-dione (324 mg, 10.58%) as a gray solid. LMS (ESI) (C 16 H 20 FN3O3)[M+1] + Calculated value: 322.1; Measured value: 322.2. 1 H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.22-7.13(m,1H),6.84-6.72(m,1H),6.01(s,2H),3.79-3.72(m,2H), 3.66-3.58(m,2H),3.28(s,2H),2.75-2.65(m,4H),1.76-1.69(m,2H),1.56-1.52(m,1H),1.31-1.03(m,2H).

[0431] Step 6: To a mixture of 1-{2-fluoro-4-[4-(hydroxymethyl)piperidin-1-yl]phenyl}-1,3-diazinan-2,4-dione (100 mg, 0.31 mmol, 1 equiv.) in DCM (5 mL) was added Dess-Martin (197 mg, 0.47 mmol, 1.5 equiv.) portionwise at 0° C. The resulting mixture was stirred at 0° C. for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by C18 reverse phase column using ACN / H2O (1 / 2). This gave the title compound as a brown solid (36 mg, 37.3%). LCMS (ESI) (C 16 H 18 FN3O3)[M+1] +Calculated value: 320.1; Measured value: 320.2.

[0432] HA-7: 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde

[0433] [ka]

[0434] Step 1: To a solution of compound 1-bromo-4-iodobenzene (50.0 g, 176 mmol, 1.00 equiv.) in DMSO (250 mL) was added piperidin-4-ylmethanol (2 To the resulting solution, KPO (6.4 g, 229 mmol, 1.30 equiv), KPO (75.0 g, 353 mmol, 2.00 equiv), CuI (6.73 g, 35.3 mmol, 0.200 equiv), and L-proline (4.64 g, 35.3 mmol, 0.200 equiv) were added at 20 °C under N. The reaction mixture was stirred at 80 °C under N for 12 h. The mixture was cooled to 20 °C and poured into water (1.00 L). The mixture was stirred for 0.5 h. The mixture was diluted with ethyl acetate (500 mL). * The organic layer was extracted with NH₃·H₂O in H₂O (100 mL of NH₃·H₂O in 700 mL of H₂O) (250 mL * The combined organic layers were washed with brine (1000 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 2 / 1, R f =0.30) to give the desired product (31.0 g, 87.0 mmol, 49.2% yield) as a yellow solid. LCMS: m / z=270.0 (M+H) + .

[0435] Step 2: To a solution of (1-(4-bromophenyl)piperidin-4-yl)methanol (30.0 g, 84.2 mmol, 1.00 equiv) and 2,6-bis(benzyloxy)-3-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)pyridine (35.1 g, 84.2 mmol, 1.00 equiv) in dioxane (300 mL) and HO (60.0 mL) at 20 °C under N was added KCO (34.9 g, 252 mmol, 3.00 equiv) and Pd(dppf)Cl·CHCl (6.88 g, 8.43 mmol, 0.100 equiv). The reaction was stirred at 110 °C under N for 12 h. The reaction was cooled to 20 °C and filtered. The filtrate was concentrated. The crude product was purified by recrystallization from MeOH (100 mL) at 20 °C for 30 min. The mixture was filtered, and the filter cake was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1, R f =0.30) to give the desired product (22.5 g, 44.8 mmol, 53.2% yield) as a yellow solid. LCMS: m / z=481.2 (M+H) + .

[0436] Step 3: To a solution of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol (20.0 g, 39.8 mmol, 1.00 equiv) and AcOH (7.18 g, 119 mmol, 6.84 mL, 3.00 equiv) in THF (200 mL) and EtOH (200 mL) was added Pd / C (5.00 g, 39.8 mmol, 10% purity, 1.00 equiv) and Pd(OH) (4.79 g, 34.1 mmol, 8.56 e-1 equiv) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 80 °C under H (50 psi) for 12 h. The mixture was cooled to 20 °C and filtered. The filtrate was concentrated. The crude product was triturated with petroleum ether / ethyl acetate = 5 / 1 (200 mL) at 20 °C for 30 minutes to give the desired product (8.00 g, 24.2 mmol, 60.7% yield) as a white solid. LCMS: m / z = 303.2 (M+H). + .

[0437] Step 4: To a solution of 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (8.60 g, 28.4 mmol, 1.00 equiv) in DMSO (90.0 mL) was added Dess-Martin periodinane (24.1 g, 56.8 mmol, 17.6 mL, 2.00 equiv) slowly at 20 °C. The reaction was stirred at 20 °C for 12 h. The mixture was adjusted to pH = 10 with saturated aqueous Na2CO3, and the aqueous layer was extracted with ethyl acetate (350 mL). * The crude product was triturated with ethyl acetate (100 mL) at 20 °C for 30 min. HA-7 (7.18 g, 22.8 mmol, 48.1% yield) was obtained as an off-white solid. LCMS: m / z = 299.1 (M−H). + . 1 H NMR:(400MHz,DMSO-d6)δ11.00-10.57(m,1H),9.80-9.35(m,1H),7.09-6.98 (m,2H),6.95-6.83(m,2H),3.79-3.66(m,1H),3.63-3.49(m,2H),2.89-2.72( m, 2H), 2.70-2.59 (m, 1H), 2.48-2.38 (m, 2H), 2.17-1.89 (m, 4H), 1.65-1.47 (m, 2H).

[0438] HA-8: rac-(R)-2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetic acid

[0439] [ka]

[0440] Step 1: To a 40 mL vial was added rac-(3R)-3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (1.00 g, 4.80 mmol), tert-butyl 2-(piperidin-4-yl)acetate (1.01 g, 5.04 mmol), DMSO (7.00 mL), and N,N-diisopropylethylamine (3.18 mL, 2.48 g, 19.21 mmol). The reaction mixture was stirred at 130° C. for 16 hours. The reaction mixture was then diluted with EtOAc and brine. The product was extracted with EtOAc (2×). The combined organic layers were washed with brine (3×), dried over MgSO4, and then concentrated. The resulting residue was purified by column chromatography (80 g silica, 0-100% EtOAc / DCM) to afford rac-tert-butyl 2-(1-{5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetate as a brown solid (456 mg, 25%). LCMS C 17 H 21 N3O4 theoretical value: 387.2, actual value: 388.2 [M+H] + .

[0441] Step 2: To a 40 mL vial was added rac-tert-butyl 2-(1-{5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)acetate (456.00 mg, 1.18 mmol) and DCM (5.00 mL). Trifluoroacetic acid (5.00 mL, 7.45 g, 65.34 mmol) was added dropwise to the reaction mixture. After 30 min, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography (100 g C18 silica, 0-20% MeCN / HO) to afford the title compound as a white solid (1.04 g, 100%). LCMS C 21 H 29 N3O4 theoretical value: 331.2, measured value: m / z = 332.2 [M+H] + .

[0442] HA-9: rac-1-[5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl]piperidine-4-carboxylic acid.

[0443] [ka]

[0444] Step 1: To a mixture of 5-bromo-2-fluoropyridine (6.64 g, 37.73 mmol, 1 equiv.) in DMF (50 mL) was added tert-butyl piperidine-4-carboxylate (8.39 g, 45.28 mmol, 1.2 equiv.) and K2CO3 (10.43 g, 75.46 mmol, 2 equiv.). The resulting mixture was stirred at 90 °C overnight. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1). This afforded tert-butyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate as a light yellow solid (10 g, 46.60% yield). LCMS (ESI) (C 15 H 21 BrN2O2)[M+H] + Calculated value: 341.2; Measured value: 341.2.

[0445] Step 2: To a mixture of tert-butyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate (2.40 g, 7.04 mmol, 1.6 equiv.), 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (1.47 g, 4.39 mmol, 1.00 equiv.), and KCO (1.2 g, 8.70 mmol, 2 equiv.) in THF (10 mL) and HO (10 mL) was added Pd(PPh) (0.5 g, 0.43 mmol, 0.1 equiv.). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere in a microwave oven for 40 minutes. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1). This gave tert-butyl 1-[2,6-bis(benzyloxy)-[3,3-bipyridin]-6-yl]piperidine-4-carboxylate as a white solid (1.2 g, 49.36% yield). LCMS (ESI) (C 33 H 35 N3O4)[M+H] + Calculated value: 552.3; Measured value: 552.0.

[0446] Step 3: To a mixture of tert-butyl 1-[2,6-bis(benzyloxy)-[3,3-bipyridin]-6-yl]piperidine-4-carboxylate (1.8 g, 3.26 mmol, 1 equivalent) in EtOH (50 mL) and THF (50 mL) was added Pd / C (0.9 g). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography using CH3CN / HO (2 / 1). This afforded tert-butyl 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carboxylate as a yellow solid (390 mg, 28.81% yield). LCMS (ESI) (C 20 H 27 N3O4)[M+H] + Calculated value: 374.2; Measured value: 374.2.

[0447] Step 4: To a mixture of tert-butyl 1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperidine-4-carboxylate (650 mg, 1.74 mmol, 1 equiv.) in DCM (100 mL) was added TFA (10 mL) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by C18 reverse-phase column chromatography using CH3CN / HO (1 / 1). This afforded rac-1-[5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl]piperidine-4-carboxylic acid as a purple solid (540.8 mg, 96.08% yield). LCMS (ESI) (C 16 H 19 N3O4)[M+H] + Calculated value: 318.2; Measured value: 318.2. 1 H NMR(300MHz,DMSO-d6)δ10.91(s,1H),7.97-7.73(m,2H),7.30(d,J=9.3Hz,1H),4.14-4.02(m,2H),3.95-3 .84(m,1H),3.29-3.14(m,2H),2.76-2.48(m,3H),2.36-2.16(m,1H),2.02-1.88(m,3H),1.70-1.51(m,2H).

[0448] HA-10: rac-(R)-3-(6-(piperazin-1-yl)pyridin-3-yl)piperidine-2,6-dione

[0449] [ka]

[0450] Step 1: tert-Butyl piperazine-1-carboxylate (0.895 g, 4.8 mmol), 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (0.5 mg, 2.40 mmol) were combined in DMSO (0.15 M), followed by the addition of N,N-diisopropylethylamine (1.68 mL, 9.61 mmol). The vial was capped and stirred at 110 °C overnight. The reaction was then cooled to room temperature, concentrated onto silica gel, and purified by column chromatography (0 to 100% EtOAc in hexanes) to give rac-tert-butyl (R)-4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazine-1-carboxylate (0.6 g, 67%). LCMS: C 19 H 26 N4O4 theoretical value: 374.1, measured value: m / z = 375.1 [M+H] + .

[0451] Step 2: rac-tert-butyl (R)-4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazine-1-carboxylate was treated with 0.6 mL of TFA in HFIP (10 mL) and stirred at room temperature for 5 hours. LCMS showed complete conversion of the starting material. The reaction mixture was concentrated and purified by C18 reverse-phase chromatography to afford rac-(R)-3-(6-(piperazin-1-yl)pyridin-3-yl)piperidine-2,6-dione as an off-white solid (0.31 g, 71%). 1 H NMR(500MHz,DMSO)δ10.85(s,1H),8.03(d,J=2.4Hz,1H),7.56(dq,J=8.9,2.1Hz,1 H),6.98(dt,J=9.1,2.1Hz,1H),3.82(dd,J=12.4,4.9Hz,1H),3.72(t,J=5.2Hz,4H) ,3.2(t,J=5.2Hz,4H),2.70(ddd,J=17.6,13.3,5.3Hz,1H),2.56(q,J=2.8,1.9Hz, 1H),2.23(qd,J=12.6,4.2Hz,1H),2.08(s,1H),1.98(dtd,J=13.3,5.2,3.2Hz,1H). LCMS:C1 4H 18N4O2 theoretical value: 274.32, measured value: m / z = 275.1 [M+H] + .

[0452] HA-11: 3-[(3RS)-1-[5-[(3RS&)-2,6-dioxopiperidin-3-yl]pyridin-2-yl]pyrrolidin-3-yl]propanoic acid

[0453] [ka]

[0454] Step 1: To a mixture of NaH (2.65 g, 110.4 mmol, 1.1 equiv) in THF (500 mL) was added benzyl 2-(dimethoxyphosphoryl)acetate (28.51 g, 110.4 mmol, 1.10 equiv) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. To the above mixture was added tert-butyl 3-formylpyrrolidine-1-carboxylate (20 g, 100.4 mmol, 1 equiv) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The aqueous layer was extracted with EtOAc (3×500 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give tert-butyl 3-[(1E)-3-(benzyloxy)-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate (31.6 g, 77.89% yield) as a colorless oil. LCMS (ESI) (C 19 H 25 NO4) [M+H] + Calculated value: 332.1; Measured value: 332.1.

[0455] Step 2: To a mixture of tert-butyl 3-[(1E)-3-(benzyloxy)-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate (12.70 g, 38.32 mmol, 1 equiv.) in THF (200 mL) was added Pd / C (2.04 g) at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. This gave 3-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (3) as an off-white solid (9 g, crude). The crude product was used directly in the next step without further purification. LCMS (ESI) (C 12 H 21 NO4) [M+1] + Calculated value: 244.1; Measured value: 244.1.

[0456] Step 3: A mixture of 3-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (9 g, crude) in HCl / dioxane (4 mol / L, 100 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. This afforded 3-(pyrrolidin-3-yl)propanoic acid as a pink solid (5.88 g, crude). LC MS(ESI)(C7H 13 N1O2)[M+1] + Calculated value: 144.0; Measured value: 144.2.

[0457] Step 4: To a mixture of 3-(pyrrolidin-3-yl)propanoic acid (5.88 g, 41.07 mmol, 1 equiv.) and 5-bromo-2-fluoropyridine (7.23 g, 41.08 mmol, 1 equiv.) in DMF (30 mL) was added K2CO3 (8.5 g, 61.6 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column using CH3CN / H2O (1 / 2). This gave 3-[1-(5-bromopyridin-2-yl)pyrrolidin-3-yl]propanoic acid as a crude brown oil (5) (12 g, 89.67% yield). 12 H 15 BrN2O2)[M+1] + Calculated value: 299.0; Measured value: 299.0.

[0458] Step 5: To a mixture of 3-[1-(5-bromopyridin-2-yl)pyrrolidin-3-yl]propanoic acid (12 g, 40.11 mmol, 1 eq.) in DCM (100 mL) was added (Z)-N,N-diisopropyl tert-butoxymethanimidamide (24.11 g, 120.4 mmol, 3 eq.) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give tert-butyl 3-[1-(5-bromopyridin-2-yl)pyrrolidin-3-yl]propanoate (4.2 g, 28.0% yield) as a brown oil. LCMS (ESI) (C 16 H 23 BrN2O2)[M+H] + Calculated value: 355.1; Measured value: 355.0.

[0459] Step 6: To a mixture of tert-butyl 3-[1-(5-bromopyridin-2-yl)pyrrolidin-3-yl]propanoate (3 g, 8.44 mmol, 1 eq.), 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (4.25 g, 12.7 mmol, 1.5 eq.), and KCO (2.33 g, 16.89 mmol, 2 eq.) in THF (30 mL) and HO (10 mL), Pd(PPh) (0.98 g, 0.84 mmol, 0.1 eq.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 40 minutes under a nitrogen atmosphere using a microwave. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give tert-butyl 3-[1-[2,6-bis(benzyloxy)-[3,3-bipyridin]-6-yl]pyrrolidin-3-yl]propanoate (7) (2.6 g, 53.34% yield) as a colorless oil. LCMS (ESI) (C 35 H 39 N3O4)[M+H] + Calculated value: 566.3; Measured value: 566.2.

[0460] Step 7: To a mixture of tert-butyl 3-[1-[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl]pyrrolidin-3-yl]propanoate (2.10 g, 3.71 mmol, 1 equivalent) in THF (6 mL) and EtOH (6 mL) was added Pd / C (1.70 g). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / EtOAc (1 / 2) to give tert-butyl 3-[1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]pyrrolidin-3-yl]propanoate (400 mg, 26.42% yield) as a colorless solid. MS (ESI) (C 21 H 29 N3O4)[M+1] + Calculated value: 388.2; Measured value: 388.3.

[0461] Step 8: tert-Butyl 3-[1-[5- A mixture of (2,6-dioxopiperidin-3-yl)pyridin-2-yl]pyrrolidin-3-yl]propanoate (490 mg, 1.27 mmol, 1 equivalent) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. This afforded 3-[(3RS)-1-[5-[(3RS)-2,6-dioxopiperidin-3-yl]pyridin-2-yl]pyrrolidin-3-yl]propanoic acid HCl salt (HA-11) (379.1 mg, 81.56%) as a white solid. LCMS (ESI) (C 17 H 21 N3O4)[M+H] + Calculated value: 332.2; Measured value: 332.1. 1 H NMR(300MHz,DMSO-d6)δ13.61(s,1H),10.93(s,1H),7.95-7.85(m,1H),7 .82(d,J=2.1Hz,1H),7.11-7.01(m,1H),4.02-3.90(m,1H),3.80-3.69(m, 2H),3.69-3.61(m,1H),3.21-3.09(m,1H),2.77-2.48(m,1H),2.47-2.37( m,1H),2.36-2.19(m,3H),2.17(s,1H),2-1.89(m,1H),1.87-1.59(m,4H).

[0462] HA-12: rac-(R)-1-(5-((R)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbaldehyde

[0463] [ka]

[0464] Step 1: To a 40 mL vial was added rac-(3R)-3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (1000.00 mg, 4.80 mmol), rac-(3R)-pyrrolidin-3-ylmethanol (485.84 mg, 4.80 mmol), N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol), and DMSO (7.00 mL). The reaction mixture was stirred at 115° C. for 16 hours. The reaction mixture was then concentrated under reduced pressure and then purified by reverse phase column chromatography (415 g C18 silica, 0-10% MeCN / water + 0.1% TFA) to give (3RS&)-3-{6-[(3RS)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridin-3-yl}piperidine-2,6-dione; trifluoroacetic acid as an amorphous solid (954 mg, 69%). LCMS C 15 H 19 N3O3 theoretical value: 289.1, measured value: m / z = 290.1 ​​[M+H] + .

[0465] Step 2: To a 200 mL RBF was added (3RS&)-3-{6-[(3RS)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridin-3-yl}piperidine-2,6-dione; trifluoroacetic acid (954.00 mg, 2.37 mmol), sodium bicarbonate (0.99 g, 11.83 mmol), and DCM (50.00 mL). The reaction mixture was cooled to 0° C., and then 1,1-bis(acetyloxy)-3-oxo-1lambda 5,2-benziodoxol-1-yl acetate (1.10 g, 2.60 mmol) was added in one portion. The reaction was stirred for 3 hours while warming to room temperature. The crude reaction mixture was adsorbed onto silica and purified by FC (40 g silica, 50-100% EtOAc / DCM+1% TEA) to give the title compound as a white solid (177 mg, 26%). 15 H 17 N3O3 theoretical value: 287.1, measured value: m / z = 288.0 [M+H] + .

[0466] HA-13: 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbaldehyde

[0467] [ka]

[0468] Step 1: To a solution of piperidin-4-ylmethanol (24.3 g, 211 mmol, 1.00 equiv.) and 3,5-dibromopyridine (50.0 g, 211 mmol, 1.00 equiv.) in DMSO (400 mL) was added KPO (89.6 g, 422 mmol, 2.00 equiv.), CuI (8.04 g, 42.2 mmol, 0.200 equiv.), and L-proline (5.54 g, 42.2 mmol, 0.200 equiv.) under N at 20 °C. The mixture was stirred at 80 °C under N for 12 h. The mixture was cooled to 20 °C and poured into water (1.00 L). The mixture was stirred at 20 °C for 0.5 h. The mixture was diluted with ethyl acetate (500 mL). * The organic layer was washed with brine (1.00 L), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1, R f =0.35) to give the desired product (33.0 g, 119 mmol, 56.5% yield) as an orange solid. LCMS: m / z=270.8 (M+H) + 。

[0469] Step 2: To a solution of (1-(5-bromopyridin-3-yl)piperidin-4-yl)methanol (20.0 g, 72.3 mmol, 1.00 equiv) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30.2 g, 72.3 mmol, 1.00 equiv) in dioxane (250 mL) and HO (50.0 mL) was added Pd(dppf)Cl·CHCl (5.91 g, 7.24 mmol, 0.100 equiv) and KCO (30.0 g, 217 mmol, 3.00 equiv) under N at 20 °C. The mixture was degassed and then stirred at 100 °C under N for 12 h. The reaction was cooled to 20 °C and concentrated. The residue was poured into water (500 mL) and ethyl acetate (500 mL * The combined organic layers were washed with brine (1000 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 1 / 3, R f =0.30) to give the desired product (25.0 g, 51.3 mmol, 70.9% yield) as a yellow solid. LCMS: m / z=482.1 (M+H) + .

[0470] Step 3: To a solution of the compound (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridin]-5-yl)piperidin-4-yl)methanol (24.0 g, 49.2 mmol, 1.00 equiv.) and AcOH (8.88 g, 147 mmol, 8.46 mL, 3.00 equiv.) in THF (120 mL) and EtOH (120 mL), 10 wt% Pd / C (6.00 g, 49.2 mmol, 1.00 equiv.) and 20 wt% Pd(OH) (5.93 g, 8.45 mmol, 0.17 equiv.) were added under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 80 °C under H (50 psi) for 12 h. The mixture was cooled to 20 °C and filtered. The filtrate was concentrated. The residue was adjusted to pH 10 with saturated aqueous Na2CO3, and the aqueous layer was extracted with ethyl acetate:THF (1:1, 1000 ml L *5). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, and concentrated in vacuo. The desired product (9.91 g, 24.1 mmol, 48.9% yield) was obtained as a pink solid without further purification. LCMS: m / z=304.2 (M+H). + .

[0471] Step 4: To a solution of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (9.91 g, 24.1 mmol, 1.00 equiv) in DMSO (100 mL) was added DMP (20.4 g, 48.2 mmol, 14.93 mL, 2.00 equiv) portionwise at 20 °C. The reaction was stirred at 20 °C for 1 h. The mixture was poured into water (100 mL) and ethyl acetate (100 mL). The mixture was adjusted to pH = 10 with saturated aqueous Na2CO3, and the aqueous layer was diluted with ethyl acetate (1000 mL). * 5) and THF:MeOH (1:1, 1000 mL * The crude product was triturated with ethyl acetate (100 mL) at 20 °C for 30 min. HA-13 (4.92 g, 16.0 mmol, 66.5% yield) was obtained as an off-white solid. LCMS: m / z = 300.1 (M−H). + . 1 H NMR:(400MHz,CDCl3)δ9.72(s,1H),8.34-8.21(m,2H),7.99(d,J=1.8Hz,1H),7.02(t,J=2.2Hz,1H),3.77-3.72(m,1H),3.68-3.61(m,2H) ),3.00-2.92(m,2H),2.84-2.76(m,1H),2.75-2.65(m,1H),2.50-2.41(m,1H),2.34-2.24(m,2H),2.11-2.04(m,2H),1.82-1.74(m,2H).

[0472] HA-14: rac-(R)-2-(1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetaldehyde

[0473] [ka]

[0474] Step 1: A 40 mL vial was charged with rac-(3R)-3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (1500.00 mg, 7.20 mmol), 4-piperidineethanol (977.44 mg, 7.57 mmol), N,N-diisopropylethylamine (5.03 mL, 3.72 g, 28.82 mmol), and DMSO (10.00 mL). The mixture was stirred at 130° C. for 16 hours. The reaction mixture was concentrated and the resulting residue was purified by reverse-phase column chromatography (415 g C18 silica, 5-50% MeCN / HO+0.1% TFA) to afford rac-(3R)-3-{6-[4-(2-hydroxyethyl)piperidin-1-yl]pyridin-3-yl}piperidine-2,6-dione; trifluoroacetic acid as an amorphous solid (2.10 g, 92% yield). LCMS C 17 H 23 N3O3 theoretical value: 317.2, measured value: 318.2 [M+H] + .

[0475] Step 2: To a 40 mL vial was added rac-(3R)-3-{6-[4-(2-hydroxyethyl)piperidin-1-yl]pyridin-3-yl}piperidine-2,6-dione; trifluoroacetic acid (1600.00 mg, 3.71 mmol); and DCM (30.00 mL). The reaction mixture was cooled to 0° C., and then 1,1-bis(acetyloxy)-3-oxo-1lambda 5,2-benziodoxol-1-yl acetate (1.73 g, 4.08 mmol) was added in one portion. After 10 min, the ice bath was removed and the reaction was allowed to warm to room temperature. The mixture was stirred for 1 hour. 3 mL of TEA was added to the reaction mixture, and the crude reaction mixture was adsorbed onto silica and then purified by column chromatography (80 g silica, 20-100% EtOAc + 1% TEA / DCM) to give the title compound as a white solid (278 mg, 47% yield). LCMS C 17 H 21 N3O3 theoretical value: 315.2, measured value: m / z = 316.2 [M+H] + .

[0476] HA-15: rac-(R)-2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetic acid

[0477] [ka]

[0478] Step 1: To a 40 mL vial was added rac-(3R)-3-(2-fluoropyridin-4-yl)piperidine-2,6-dione (1000.00 mg, 4.80 mmol), tert-butyl 2-(piperazin-1-yl)acetate (1443.01 mg, 7.20 mmol), DMSO (7.00 mL), and N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol). The reaction mixture was stirred at 120° C. for 3 hours. The reaction mixture was diluted with brine and EtOAc. The product was extracted with EtOAc (2×), and the combined organic layers were washed with brine (4×), dried over MgSO4, and then concentrated. The resulting residue was purified by column chromatography (80 g silica, 30-100% EtOAc / DCM+1% TEA) to afford rac-tert-butyl 2-(4-{4-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperazin-1-yl)acetate as an off-white solid (1.454 g, 78% yield). LCMS C 20 H 28 N4O4 theoretical value: 388.2, measured value: m / z = 389.2 [M+H] + .

[0479] Step 2: To a 40 mL vial was added rac-tert-butyl 2-(4-{4-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperazin-1-yl)acetate (1454.30 mg, 3.74 mmol), HFIP (5.00 mL), and trifluoroacetic acid (2.85 mL, 4.27 g, 37.44 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated. The resulting residue was purified by RP-FC (100 g C18 silica, 0-10% MeCN / HO) to give the title compound as a white solid (813 mg, 65% yield). LCMS C 16 H 20 N4O4 theoretical value: 332.1, measured value: m / z = 333.1 [M+H] + .

[0480] HA-16: rac-(R)-1-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid

[0481] [ka]

[0482] Step 1: In a 40 mL vial, add rac-(3R)-3-(2-fluoropyridin-4-yl)piperidine-2,6-dione (1000 mg, 4.80 mmol), tert-butyl 2-(2-fluoropyridin-4-yl)piperidine-2,6-dione (1000 mg, 4.80 mmol), To the resulting mixture was added ethyl piperidine-4-carboxylate (978.87 mg, 5.28 mmol), N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol), and DMSO (7.00 mL). The reaction mixture was stirred at 120° C. for 16 hours. The reaction mixture was diluted with EtOAc and brine. The product was extracted with EtOAc (2×). The combined organic layers were washed with brine (4×), dried over MgSO4, and then concentrated. The resulting residue was purified by column chromatography (80 g silica, 0–70% EtOAc / DCM) to afford rac-tert-butyl 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4-carboxylate as an off-white solid (1.235 g, 69% yield). LCMS C 20 H 27 N3O4 theoretical value: 373.2, measured value: m / z = 374.2 [M+H] + .

[0483] Step 2: To a 40 mL vial was added rac-tert-butyl 1-{4-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidine-4-carboxylate (630.00 mg, 1.69 mmol) and HFIP (4.00 mL). Trifluoroacetic acid (1.28 mL, 1.92 g, 16.87 mmol) was added dropwise to the reaction mixture. After 2 h, the reaction mixture was concentrated. The resulting residue was purified by reverse-phase column chromatography (100 g C18 silica, 0-15% MeCN / HO) to afford the title compound as a white solid (408 mg, 76% yield). LCMS C 16 H 19 N3O4 theoretical value: 317.1, measured value: m / z = 318.1 [M+H] + .

[0484] HA-17: rac-(R)-1-(5-((R)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carboxylic acid

[0485] [ka]

[0486] Step 1: A 40 mL vial was charged with rac-(3R)-3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (1000.00 mg, 4.80 mmol), rac-tert-butyl (3R)-pyrrolidine-3-carboxylate (822.51 mg, 4.80 mmol), N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol), and DMSO (7.00 mL). The mixture was stirred at 115° C. for 16 hours. The reaction mixture was then diluted with EtOAc and brine. The product was extracted with EtOAc (2x) and the combined organic layers were washed with brine (4x), dried over MgSO4, and then purified by column chromatography (80 g silica, 10-100% EtOAc / DCM) to afford tert-butyl (3RS)-1-{5-[(3RS&)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}pyrrolidine-3-carboxylate as a white solid (779.1 mg, 45% yield). LCMS C 19 H 25 N3O4 theoretical value: 359.2, measured value: m / z = 360.2 [M+H] + .

[0487] Step 2: To a 40 mL vial was added tert-butyl (3RS)-1-{5-[(3RS&)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}pyrrolidine-3-carboxylate (779.10 mg, 2.17 mmol), HFIP (4.00 mL), and trifluoroacetic acid (1.65 mL, 2.47 g, 21.68 mmol). The reaction mixture was stirred for 4 hours and then concentrated. The resulting residue was purified by reverse-phase chromatography (100 g C18 silica, 0-10% MeCN / water) to afford the title compound as a white solid (589 mg, 90% yield). LCMS C 15 H 17 N3O4 theory Theoretical value: 303.1, Measured value: m / z = 304.0 [M+H] + .

[0488] HA-18: rac-(R)-3-(6-(piperidin-4-yloxy)pyridin-3-yl)piperidine-2,6-dione

[0489] [ka]

[0490] Step 1: tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.14 g, 5.68 mmol) was dissolved in NMP (10 mL) and the reaction was cooled to 0 °C. Sodium hydride (0.27 g, 11.36 mmol) was added and the reaction was stirred for 5 minutes, after which 5-bromo-2-fluoropyridine (0.58 mL, 1.00 g, 5.68 mmol) was added. The reaction was heated to 60 °C for 4 hours. The product was purified by reverse-phase flash column chromatography (0-100% acetonitrile in water) by direct injection to give tert-butyl 4-[(5-bromopyridin-2-yl)oxy]piperidine-1-carboxylate (0.751 g, 37% yield). LCMS: C 15 H 21 BrN2O3 theoretical value 357.25, measured value: m / z = 358.10 [M+H] + .

[0491] Step 2: tert-Butyl 4-[(5-bromopyridin-2-yl)oxy]piperidine-1-carboxylate (0.750 g, 2.10 mmol), Pd(dppf)Cl·DCM (0.342 g, 0.42 mmol), cesium carbonate 1N solution (5.25 mL, 1.71 g, 5.25 mmol), 2,6-bis(benzyloxy)pyridin-3-ylboronic acid (0.703 g, 2.10 mmol), and dioxane (5.00 mL) were combined in a sealed vial. The vial was purged with nitrogen gas and stirred at 100 °C for 60 min. The reaction was poured into brine, extracted with ethyl acetate, filtered, and concentrated onto silica gel. The reaction was purified by flash column chromatography (0-100% ethyl acetate in hexanes) to give tert-butyl 4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl]oxy}piperidine-1-carboxylate (1.05 g, 88% yield). LCMS: C 34 H 37 N3O5 theoretical value 567.69, measured value: m / z = 568.70 [M+H] + .

[0492] Step 3: tert-Butyl 4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl]oxy}piperidine-1-carboxylate (1.05 g, 1.8 mmol) was dissolved in EtOH (20.00 mL). Palladium on carbon 10% (0.20 g, 0.18 mmol) was added and the reaction was stirred under a hydrogen balloon for 12 hours. The reaction was filtered through Celite and concentrated to give tert-butyl 4-({5-[(3R)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}oxy)piperidine-1-carboxylate (0.647 g, 95%). LCMS: C 20 H 27 N3O5 theoretical value: 389.45, measured value: m / z = 390.20 [M+H] + .

[0493] Step 4: tert-Butyl 4-({5-[(3R)-2,6-dioxopiperidine-3 (3R)-3-[6-(piperidin-4-yloxy)pyridin-3-yl]piperidine-2,6-dione (0.427 g, 92% yield). LCMS: C 15 H 19 N3O3 theoretical value: 289.34, measured value: m / z = 290.20 [M+H] + .

[0494] HA-19: 1-[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]piperidine-4-carbaldehyde

[0495] [ka]

[0496] Step 1: A mixture of 2-fluoro-4-nitropyridine (20 g, 0.140 mol, 1 eq.), piperidin-4-ylmethanol (24.318 g, 0.211 mol, 1.5 eq.) and DIPEA (27.29 mL, 0.211 mol, 1.5 eq.) in anhydrous DMSO (50 mL, 2.82 M) was stirred at 90° C. overnight. The reaction mixture was slowly poured into ice water. The resulting precipitate was filtered and purified by FC (DCM / MeOH-9 / 1) to give 33.37 g of [1-(5-nitropyridin-2-yl)piperidin-4-yl]methanol (47% yield) as a yellow solid. LCMS: (M+H) + =237.7 1H NMR(300MHz,CDCl3)δ9.05(d,J=2.8Hz,1H),8.20(dd,J=9.6,2.8Hz,1H),6.60(d,J=9.6Hz,1H),4.59(d,J=13 .4Hz,2H),3.57(d,J=5.9Hz,2H),3.11-2.95(m,2H),1.98-1.84(m,3H),1.31(tdd,J=14.3,11.8,4.2Hz,2H).

[0497] Step 2: [1-(5-nitropyridin-2-yl)piperidin-4-yl]methanol (15.5 g, 0.065 mol, 1 equiv.) was dissolved in a mixture of EtOH / MeOH-1 / 1 (250 mL, 0.26 M), degassed, and charged with Pd / C (50% wet, 2.32 g, 15% by weight). The reaction mixture was evacuated, refilled with H2, and left stirring overnight (balloon, 1 atm), then filtered through a Celite pad and concentrated to give 5.85 g of [1-(5-aminopyridin-2-yl)piperidin-4-yl]methanol (45% yield) as a pale yellow oil, which was used in the next step without further purification. LCMS (M+H) + =208.25 1 H NMR(300MHz,DMSO-d6)δ7.59(dd,J=2.9,0.7Hz,1H),6.89(dd,J=8.8,2.9Hz,1H),6.61(dd,J=8.9,0.8Hz,1H),4.56-4.39(m,3H), 4.02-3.89(m,2H),3.26(dd,J=6.3,5.3Hz,2H),2.60-2.52(m,2H),1.76-1.62(m,2H),1.49(s,1H),1.12(dd,J=12.2,4.0Hz,2H).

[0498] Step 3: In a pressure vessel, [1-( [5-aminopyridin-2-yl]piperidin-4-yl]methanol (5.8 g, 27.9 mmol, 1 eq.) and acrylic acid (1.9 mL, 27.9 mmol, 1 eq.) were charged. The resulting reaction mixture was stirred at 90° C. After 16 h, 25% of the starting amine was still present. An additional 0.25 eq. of acrylic acid was added, and the reaction mixture was stirred at 90° C. for an additional 16 h. The mixture was then concentrated, and the resulting residue was diluted with EtOAc, refluxed, and the solution decanted. The residue (a black gum) was redissolved in MeOH and evaporated to give 6.4 g of 3-({6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl}amino)propanoic acid (78% yield). LCMS (M+H) + =280.25. (MH) - =278.025. 1 H NMR(300MHz,DMSO-d6)δ7.59(d,J=2.9Hz,1H),6.93(dd,J=8.9,3.0Hz,1H),6.68(d,J=8.9Hz,1H),4.00(dt,J=12.8,3.3Hz,2H) ,3.39(t,J=7.1Hz,1H),3.26(d,J=6.3Hz,3H),2.63-2.53(m,2H),2.47-2.29(m,3H),1.67(s,2H),1.13(dd,J=12.2,4.0Hz,2H).

[0499] Steps 4 and 5: 3-({6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl}amino)propanoic acid (6.4 g, 21.76 mmol, 1.0 equiv.) and urea (2.614 g, 43.53 mmol, 2.0 equiv.) were dissolved in glacial acetic acid (64 mL, 10 vol.) and stirred at 90 °C for 48 h. The reaction mixture was concentrated, and the resulting residue was dissolved in EtOH (100 mL). H2SO4 (0.012 mL, 0.022 mmol, 0.01 equiv.) was added, followed by stirring at room temperature for 48 h. The pH of the reaction mixture was adjusted to pH = 10-11 with KHSO4, concentrated, and purified by chromatography (DCM / MeOH - 9 / 1). The resulting material was further triturated with DCM to give 1.28 g of 1-{6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl}-1,3-diazinan-2,4-dione (18% yield). LCMS (M+H) + =305.05. 1 H NMR(300MHz,DMSO-d6)δ10.34(s,1H),8.04(d,J=2.7Hz,1H),7.47(dd,J=9.0,2.8Hz,1H),6.84(d,J=9.1Hz,1H),4.47(t,J=5.3Hz, 1H),4.29(d,J=13.0Hz,2H),3.70(t,J=6.7Hz,2H),3.27(t,J=5.7Hz,2H),2.83-2.65(m,4H),1.77-1.54(m,3H),1.18-1.03(m,2H).

[0500] Step 6: To 1-{6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl}-1,3-diazinan-2,4-dione (0.715 g, 2.3 mmol, 1 equiv.) dissolved in anhydrous DCM (0.3 M) was added a solution of Dess-Martin periodinane (1.073 g, 2.53 mmol, 1.1 equiv.) in anhydrous DCM (0.15 M) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h (TLC and LCMS control). The reaction mixture was diluted with saturated aqueous NaSO, and the organic layer was separated and washed with saturated NaHCO. The aqueous layers were combined and back-extracted several times with DCM. The combined organic phases were dried over NaSO and concentrated to give 0.56 g of 1-[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]piperidine-4-carbaldehyde (HA-19) (77% yield) as a beige solid. The product tends to form a stable hydrate. 1 H NMR(300MHz,DMSO-d6)δ10.35(s,1H),9.63(d,J=0.9Hz,1H),8.08-8.03(m,1H),7.50(dd,J=9.0,2.8Hz,1H),6.88(d,J=9.1Hz,1H),4.13(dt,J=13. 2,4.1Hz,2H),3.70(t,J=6.7Hz,2H),3.11-2.99(m,2H),2.71(d,J=6.7Hz ,2H),2.66-2.55(m,1H),1.90(dd,J=13.3,3.9Hz,2H),1.55-1.42(m,2H). LCMSESI(+)[M+H] + =305.11.

[0501] HA-20: rac-(R)-1-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehyde

[0502] [ka]

[0503] Step 1: To a 40 mL vial was added rac-(3R)-3-(2-fluoropyridin-4-yl)piperidine-2,6-dione (1.0 g, 4.80 mmol), piperidin-4-ylmethanol (0.59 g, 5.04 mmol), N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol), and DMSO (7.00 mL). The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was then concentrated and purified by RP-FC (415 g C silica, 5-20% MeCN / HO + 0.1% TFA) to give rac-(3R)-3-{2-[4-(hydroxymethyl)piperidin-1-yl]pyridin-4-yl}piperidine-2,6-dione; trifluoroacetate (1.73 g, quantitative yield) as a white solid. LCMS.C 16 H 21 N3O3 theoretical value: 303.2, measured value: m / z = 304.5 [M+H] + .

[0504] Step 2: A 200 mL flask was charged with rac-(3R)-3-{2-[4-(hydroxymethyl)piperidin-1-yl]pyridin-4-yl}piperidine-2,6-dione; trifluoroacetic acid (1.71 g, 4.10 mmol), DCM (50.00 mL), and MeCN (10.00 mL). The reaction mixture was cooled to 0° C., and 1,1-bis(acetyloxy)-3-oxo-1-lambda-5,2-benziodoxol-1-yl acetate (1.91 g, 4.51 mmol) was added in one portion. After stirring at 0° C. for 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. 3 mL of TEA was added to the reaction mixture, then the crude mixture was absorbed onto silica and then purified by column chromatography (120 g silica, 10-100% EtOAc / DCM) to give the title compound as a white solid (233 mg, 18%). LCMS C 16 H 19 N3O3 theoretical value: 301.1, measured value: m / z = 302.1 [M+H] + .

[0505] HA-21: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde

[0506] [ka]

[0507] Step 1: To a 40 mL vial was added 1-(4-bromophenyl)-1,3-diazinan-2,4-dione (6.40 g, 24 mmol), cesium carbonate (9.30 g, 28.5 mmol), and DMF (60.00 mL). To the reaction mixture was added 4-methoxybenzyl chloride (4.17 mL, 4.84 g, 30.9 mmol). The reaction mixture was stirred overnight and then quenched with water. The product was extracted with DCM (3x), dried over Na2SO4, and then concentrated. The resulting residue was purified by FC (330 g silica, 0-50% EtOAc / DCM). The purified residue was concentrated under reduced pressure to give an amorphous solid. and triturated with hexane to give 1-(4-bromophenyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione as a white solid (9.26 g, quantitative yield). LCMS: C 18 H 17 BrN2O3 theoretical value: 388.0, measured value: m / z = 389.2 [M+H] + .

[0508] Step 2: To a 2-dram vial was added 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (550 mg, 1.41 mmol), 4-(1,3-dioxolan-2-yl)piperidine (666 mg, 4.24 mmol), di-tert-butyl({2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl})phosphane (240 mg, 0.57 mmol), palladium(II) acetate (63 mg, 0.28 mmol), cesium carbonate (1.38 g, 4.24 mmol), and dioxane (5.00 mL). The reaction mixture was sparged with N for 10 minutes and then stirred at 95 °C overnight. The crude reaction mixture was diluted with DCM and water and then filtered through Celite. The product was extracted with DCM (3x), dried over MgSO4, and concentrated. The resulting residue was purified by FC (40 g silica, 0-100% EtOAc / hex) to give 1-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)phenyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione as a white solid (395 mg, 60%). LCMS: C 26 H 31 N3O5 theoretical value: 465.2, measured value: m / z = 466.4 [M+H] + .

[0509] Step 3: To a 20 mL vial was added 1-{4-[4-(1,3-dioxolan-2-yl)piperidin-1-yl]phenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (395 mg, 0.85 mmol) and TFA (5.00 mL). To the reaction mixture was added trifluoromethanesulfonic acid (374 μL, 636 mg, 4.24 mmol). Complete conversion was achieved after 10 min. The reaction mixture was diluted with minimal water and then purified by RP-FC (415 g C18 silica, 0-50% MeCN / water + 0.1% TFA) to give 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde as a white solid (40 mg, 16%). LCMS: C 16 H 21N3O3 theoretical value: 301.1, measured value: m / z = 302.2 [M+H] + .

[0510] HA-22: 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)piperidine-4-carbaldehyde

[0511] [ka]

[0512] Step 1: To a 20 mL vial was added 3-(2,4-dioxo-1,3-diazinan-1-yl)-4-fluorobenzoic acid (150 mg, 0.59 mmol), piperidin-4-ylmethanol (69 mg, 0.59 mmol), N,N-diisopropylethylamine (0.31 mL, 0.23 g, 1.78 mmol), and DMF (2 mL). To the reaction mixture was added a solution of [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanide (226 mg, 0.59 mmol) in DMF (1 mL). The reaction mixture was stirred for 16 h, and the crude reaction mixture was purified by RP-FC (100 g C18 silica, 0.59 mmol). Purification by 30% MeCN / water + 0.1% TFA) gave 1-(2-fluoro-5-(4-(hydroxymethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione as a white solid (263 mg, quantitative yield). LCMS: C 17 H 20 FN3O4 theoretical value: 349.1, measured value: m / z = 350.2 [M+H] + .

[0513] Step 2: To a 2-dram vial was added 1-{2-fluoro-5-[4-(hydroxymethyl)piperidine-1-carbonyl]phenyl}-1,3-diazinan-2,4-dione (40 mg, 0.11 mmol), DMSO (0.50 mL), DCM (1.50 mL), and IBX polystyrene (1.22 mmol / g, 0.3 g). The reaction mixture was stirred for 1 day and then filtered with an additional 20 mL of DCM. The crude mixture was concentrated and carried on to the next step as a solution in DMSO without further purification. LCMS: C 17 H 18 FN3O4 theoretical value: 347.1, measured value: m / z = 348.3 [M+H] + .

[0514] HA-23: 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0515] [ka]

[0516] Step 1: Synthesis of 3-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)propanoic acid: To a 20 mL vial was added tert-butyl 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.0 g, 4.0 mmol), acrylic acid (0.28 mL, 290 mg, 4.0 mmol), and toluene (7.0 mL). The reaction mixture was stirred at 80° C. for 16 hours and then concentrated. The resulting crude product was used in the next step without further purification. LCMS C 17 H 24 N2O4 theoretical value: 320.2, measured value: m / z = 321.2 [M+H] + .

[0517] Step 2: Synthesis of 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)dihydropyrimidine-2,4(1H,3H)-dione: To a 40 mL vial was added 3-{[2-(tert-butoxycarbonyl)-3,4-dihydro-1H-isoquinolin-6-yl]amino}propanoic acid (1.29 g, 4.0 mmol), urea (0.48 g, 8.1 mmol), and acetic acid (2.00 mL). The reaction mixture was stirred at 120° C. for 16 hours. To the crude reaction mixture was added TFA (1 mL). The reaction mixture was stirred for 1 hour and then purified by RP-FC (415 g C18 silica, 0-20% MeCN / water) to give the title compound (126 mg, 10%) as an off-white solid. LCMS C 13 H 15 N3O2 theoretical value: 245.1, measured value: m / z = 246.1 [M+H] + .

[0518] HA-24: rac-(R)-2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid

[0519] [ka]

[0520] Step 1: To a 40 mL vial was added tert-butyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.0 g, 3.2 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.47 g, 3.52 mmol), potassium phosphate tribasic (2.04 g, 9.61 mmol), Pd(dppf)Cl·DCM (0.26 g, 0.32 mmol), dioxane (7.00 mL), and water (2.50 mL). The reaction mixture was degassed with nitrogen for 15 minutes and then stirred at 90 °C for 16 hours. The reaction mixture was then diluted with water and EtOAc and then filtered through Celite. The product was extracted with EtOAc (3x), dried over MgSO, and concentrated. The resulting residue was purified by FC (80 g silica, 0-25% EtOAc / hexane) to give tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate as a colorless oil (1.48 g, 88%). LCMS: C 33 H 34 N2O4 theoretical value: 522.3, measured value: m / z = 523.3 [M+H] + .

[0521] Step 2: To a 40 mL vial was added tert-butyl 6-[2,6-bis(benzyloxy)pyridin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.48 g, 2.83 mmol), Pd / C (700 mg), THF (10 mL), and EtOH (10 mL). The reaction mixture was sparged with hydrogen for 5 minutes, and then the reaction was stirred under a hydrogen atmosphere (balloon) for 16 hours. The reaction mixture was filtered through Celite and then concentrated. The resulting residue was purified by FC (40 g silica, 0-10% MeOH / DCM) to give tert-butyl 6-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a white solid (852 mg, 87%). LCMS: C 19 H 24 N2O4 theoretical value: 344.2, measured value: m / z = 345.2 [M+H] + .

[0522] Step 3: To a 40 mL vial was added rac-tert-butyl 6-[(3R)-2,6-dioxopiperidin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (852 mg, 2.47 mmol) and DCM (2.00 mL). To the reaction mixture was added 4 M hydrogen chloride in dioxane (6.18 mL, 0.90 g, 24.7 mmol) in a dropwise manner. After 1 hour, the reaction mixture was concentrated to give tert-butyl 6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a white solid (707 mg, quantitative yield). LCMS: C 14 H 16 N2O2 theoretical value: 244.1, measured value: m / z = 245.0 [M+H] + .

[0523] Step 4: To a 1-dram vial was added rac-(3R)-3-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-2,6-dione hydrochloride (100 mg, 0.356 mmol), N,N-diisopropylethylamine (0.31 mL, 0.23 g, 1.78 mmol), and DMF (2.00 mL). To the reaction mixture was added tert-butyl 2-bromoacetate (53 μL, 76 mg, 0.39 mmol). After stirring for 16 h, the reaction mixture was diluted with RP-FC (30 g C18 silica, 0-50% MeCN / water). +0.1% TFA) to give rac-tert-butyl (R)-2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate as a white solid (165 mg, quantitative yield). LCMS: C 20 H 26 N2O4 theoretical value: 358.2, measured value: m / z = 359.4 [M+H] + .

[0524] Step 5: To a 2-dram vial was added rac-tert-butyl 2-{6-[(3R)-2,6-dioxopiperidin-3-yl]-3,4-dihydro-1H-isoquinolin-2-yl}acetate (127 mg, 0.36 mmol), trifluoroacetic acid (0.50 mL, 0.74 g, 6.5 mmol), and DCM (0.50 mL). The reaction mixture was stirred at 40° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give rac-(R)-2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid as a white solid (149 mg, quantitative yield). LCMS: C 16 H 18 N2O4 theoretical value: 302.1, measured value: m / z = 303.3 [M+H] + .

[0525] HA-25: rac-(3R)-3-(6-{2-oxo-7-azaspiro[3.5]nonan-7-yl}pyridin-3-yl)piperidine-2,6-dione

[0526] [ka] Step 1: To a 4 mL vial was added rac-(3R)-3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (51.5 mg, 0.247 mmol), 2,2-dimethoxy-7-azaspiro[3.5]nonane (48 mg, 0.26 mmol), N,N-diisopropylethylamine (173 μL, 0.13 g, 0.99 mmol), and DMSO (0.30 mL). Stir at 130 °C for 14 h. Add additional amine (10 mg) and continue heating overnight. The solution was used directly in the next step. LCMS: ESI(+) [M+H] + =374.3

[0527] Step 2: rac-(3R)-3-(6-{2-oxo-7-azaspiro[3.5]nonan-7-yl}pyridin-3-yl)piperidine-2,6-dione. Excess DIPEA was removed from the previous reaction on a r...

Claims

1. Formula (I): 【Chemistry 1-1】 or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof, wherein: R １ is 1 to 3 R ａ C optionally substituted with １～１０ alkyl, 1 to 3 R ａ C optionally substituted with ３～１０ cycloalkyl, or 1 to 3 R ａ 4-12 membered heterocyclyl optionally substituted with L is -L １ -L ２ -L ３ -L ４ -, where: L 1 is 【Chemistry 3-1】 and -L 2 -L 3 -L 4 - has the following structure: -C(O)-, -(CH 2 ) m -, 【Chemistry 3-2】 where m is 1, 2, or 3; each R a is independently halo, —CN, C 1-3 alkyl optionally substituted with 1 to 3 R d , C 3-6 cycloalkyl optionally substituted with 1 to 3 R d , or —OR c ; each R c is independently H or C 1-3 alkyl; each R d is independently halo, oxo, —CN, —OH, C 1-6 alkyl optionally substituted with 1 to 3 fluoro, or C 3-8 cycloalkyl, or —O—C 1-6 alkyl optionally substituted with 1 to 3 fluoro; W is C(R ｇ ) or N, The B ring has the following structure: [Chemistry 1-2] and R ｇ is hydrogen or C １～６ is alkyl, However, the compound is as follows: [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] [Chemistry 1-6] or a pharmaceutically acceptable salt thereof, A bifunctional compound or a pharmaceutically acceptable salt thereof, an isotopic form, an isolated stereoisomer, or a mixture of stereoisomers.

2. 10. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof, wherein W is CH.

3. R １ teeth, a) C optionally substituted with halo, —OH, or —CN １～５ Alkyl, b) Halo, C １～５ 4-8 membered heterocyclyl optionally substituted with alkyl, —OH, or —CN; c) Halo, C １～５ C optionally substituted with alkyl, —OH, or —CN ３～１０ cycloalkyl 2. The compound of claim 1, wherein:

4. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof for treating cancer.

5. The pharmaceutical composition of claim 4, wherein the cancer is lymphoma, leukemia, acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).

6. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof for treating a metabolic disorder.

7. 7. The pharmaceutical composition of claim 6, wherein the metabolic disorder is diabetes (type I and type II diabetes), metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

8. 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof for treating an inflammatory disorder.

9. 9. The pharmaceutical composition of claim 8, wherein the inflammatory disorders include rheumatoid arthritis (RA), inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, necrotizing enterocolitis, gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, inflammation associated with gastrointestinal infections including Clostridioides difficile (C. difficile), viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and kidney diseases including chronic kidney disease and diabetic kidney disease.

Images